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Ingo Hartung Profile
Ingo Hartung

@HartungIngo

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MedChem @Merckgroup ; drug discovery nerd in oncology, immunology & targeted protein degradation, soccer, politics or tapas can get into the way; my own views

Darmstadt & Playa de Canyelles
Joined June 2017
Don't wanna be here? Send us removal request.
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@HartungIngo
Ingo Hartung
@HartungIngo
1 month
Absolutely thrilled to see early clinical data for cKit inhibitor IDRx-42 (M4205), which was discovered in our MedChem labs @merckgroup in Darmstadt. If you are interested in its discovery story, check here: #ASCO24
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Identification of M4205─A Highly Selective Inhibitor of KIT Mutations for Treatment of Unresectable...

The treatment of gastrointestinal stromal tumors (GISTs) driven by activating mutations in the KIT gene is a prime example of targeted therapy for treatment of cancer. The approval of the tyrosine...

pubs.acs.org
@schoffski
Patrick Schöffski
@schoffski
2 months
The IDRX-42 GIST story: yet another example of reverse translation of our in vivo work with patient-derived mouse xenografts in the Lab of Experimental Oncology at KU Leuven providing a rationale for a clinical application. See De Sutter et al DOI: 10.1158/1078-0432.CCR-22-3822
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
This is in my eyes the most important annual paper for students preparing for a job interview in medicinal chemistry (or process chemistry): provides a great overview about representative drug structures, their targets & synthetic routes used. @ACSBioMed
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@HartungIngo
Ingo Hartung
@HartungIngo
4 years
2020 was a very strange year, in many aspects. One being that I fulfilled a New Year resolution... @duolingo 🇪🇸 🇩🇪 🇬🇧 (🇫🇷)
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@HartungIngo
Ingo Hartung
@HartungIngo
3 years
Nope, not Pd-free. This much has become clear by now. If the amine is synthesized as described, it contains lots of Pd. If synthesized w/o touching Pd, the coupling does not work. Thanks to Johannes Krieger in our MedChem labs for some detective work. Others will report more.
@HartungIngo
Ingo Hartung
@HartungIngo
3 years
The amine-catalyzed Suzuki-Miyaura coupling published in @NatureCatalysis has caused raised eyebrows. A truly Pd-free version of this important reaction? First results from our MedChem labs show good conversions. A broader assessment definitely justified:
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@HartungIngo
Ingo Hartung
@HartungIngo
4 years
One of my favorite annual publications in @JMedChem : the compendium of synthetic routes for recently approved drugs (written by current & former chemists @pfizer ). A training guide for students & proof that drug discovery has left the flatlands @JMedChem
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
We must not stop repeating this message: synthetic chemistry innovations are the basis for many breakthroughs in small (and sometimes less small) molecule drug discovery! @ScienceMagazine
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@DocKlahn
Philipp Klahn
@DocKlahn
2 years
Next on stage at @merck_de Organic and Medicinal Chemistry Symposium Marlin Lemurell from @AstraZeneca presenting on advances of organic chemistry in drug discovery
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@HartungIngo
Ingo Hartung
@HartungIngo
4 months
Holy shit! Revolution Medicines’ #KRas G12D inhibitor RMC-9805 covalently labels the oncogenic aspartate with a aziridine warhead making use of 9 (!) stereocenters to achieve potency, selectivity & stability. My thoughts & prayers are with the process chemistry team. #AACR24
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@HartungIngo
Ingo Hartung
@HartungIngo
3 years
Big surprise at #AACR21 : The structure of AR-degrading #PROTAC #ARV110 being disclosed and the winner is: Cereblon! And not even lenalidomide-based... but it carries a magic fluoride... WOW. @ArvinasInc @AACR
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@HartungIngo
Ingo Hartung
@HartungIngo
5 months
Finally I read this viewpoint in @ACSMedChemLett . I do not disagree that successfully crafting a total synthesis is a good medicinal chemisty training ground, but how the over-competitive culture in total synthesis groups has stiffled chemistry innovation can't be ignored. (1/x)
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
Credit where credit is due. Today’s azide-based click chemistry is based on pioneering studies done more than 60 years ago in the lab of Rolf Huisgen. The impact of innovative chemistry. Rolf Huisgen died in 2020 at the age of 99. #NobelPrize @angew_chem
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
New Year‘s greetings for #chemtwitter & #ScienceTwitter followers, published on Jan 1st 🤷🏼‍♂️: „Rules were made to be broken“. 25 years since the Rule-of-5 was proposed: What is the relevance for today‘s small molecule drug discovery? @BayardHuck @NatRevChem
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@HartungIngo
Ingo Hartung
@HartungIngo
3 years
The amine-catalyzed Suzuki-Miyaura coupling published in @NatureCatalysis has caused raised eyebrows. A truly Pd-free version of this important reaction? First results from our MedChem labs show good conversions. A broader assessment definitely justified:
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
If you are as lost as I am in the onslaught of new publications about #PROTACs , here is your chance to regain some overview about what is happening: a really extensive review from the Rao group about the PROTAC target space. And it is free access! #TPD
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
I know that a scientific presentation should not be reduced to design aspects. But I liked Tanja Gaich's exceptional slide design already many years ago when I saw her present for the first time. And I still enjoy it very much (and her science is spectacular as well) #Irsee22
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@HartungIngo
Ingo Hartung
@HartungIngo
1 year
The mystery why #BRD4 is so easily degradable by various #PROTACs seems to be solved: because it doesn’t need much to glue BRD4 to the E3 ligase #DCAF16 . Stunning. I need to free up time today to read the 2 new papers @biorxivpreprint following the recent AbbVie paper @ACSBioMed !
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@HartungIngo
Ingo Hartung
@HartungIngo
1 year
Amen! A must read: @ACSBioMed #DrugDiscovery
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@HartungIngo
Ingo Hartung
@HartungIngo
1 year
A good read in Drug Discovery Today by colleagues @AstraZeneca : how is the changing landscape of targets (less ligandable, higher fraction of disordered regions) impacting approaches to identify small molecule hits. A lot is changing, for the better!
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@HartungIngo
Ingo Hartung
@HartungIngo
10 months
Innovative solutions are needed to deliver small molecule degraders specifically to diseased cells. Using degraders as ADC payloads is complicated. Introducing PROxAb shuttles, our plug-and-play solution to deliver unmodified #PROTACs #TPD @biorxivpreprint
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
Thomas Hayhow @AstraZeneca about turning a SERD into a ER-PROTAC (making use of their deep understanding of ER biology). Sharing a landmark finding in PROTAC drug discovery: linker cleavage leading to a metabolite which outcompetes the degrader in vivo! #EFMCISMC22 @EuroMedChem
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@HartungIngo
Ingo Hartung
@HartungIngo
3 years
What a beautiful piece of structure-based drug design: the discovery of #KRasG12D inhibitor #MRTX1133 . You only have to look at the crystal structures to appreciate the craftmanship with which the inhibitor was designed into the three subpockets @ACSBioMed
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@HartungIngo
Ingo Hartung
@HartungIngo
4 years
While I share the outrage about the Hudlicky „paper“, I don’t think that this wave of resignments helps. I see several names on the list below I would have rather hoped they would lead @angew_chem into a more open-minded, diversity-embracing future. Change happens from within.
@JacobsenLab
Jacobsen Lab
@JacobsenLab
4 years
Eric and other members of the @angew_chem International Advisory Board have resigned their positions on the Board.
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
More than 10 years ago the @CarreiraGroup joint forces with @Roche to make oxetanes popular in drug discovery. A new study by @jamesabull in @NatureChemistry now introduces a mild & versatile procedure for installing aryl oxetane amines as amide isosters:
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@HartungIngo
Ingo Hartung
@HartungIngo
3 years
Finally! Identifying palladium culprits in amine catalysis ⁦ @NatureCatalysis ⁩. Twitter-mediated peer review works. Now we only need to speed up the process to get such findings into print. ⁦Kudos to ⁦ @bedcatalysis ⁩ for keeping us on track.
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Identifying palladium culprits in amine catalysis

Nature Catalysis - Identifying palladium culprits in amine catalysis

www.nature.com
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@HartungIngo
Ingo Hartung
@HartungIngo
3 years
And it turns out to be a 1-2 punch for CRBN vs. VHL at #AACR21 . Also ER-degrading #PROTAC #ARV471 is employing a cereblon binder to achieve efficient ER degradation in humans & shows promise for breast cancer patients. Sorry @alessiociulli , you lost your bet. @ArvinasInc @AACR
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@HartungIngo
Ingo Hartung
@HartungIngo
1 year
A study by @genentech with huge implications for #TPD & #PROTAC space (efficacy & safety): Induced degradation of certain proteins generates peptides which bind to & induce cIAP1 autodegradation, leading to caspase activation & cell death. @biorxivpreprint
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@HartungIngo
Ingo Hartung
@HartungIngo
7 years
#AfD #bw17 Würden Sie diesen Pappnasen 9541,74 Euro pro Monat als Berater für Zukunftsfragen zahlen? Nein? Das lässt sich am So verhindern.
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@HartungIngo
Ingo Hartung
@HartungIngo
3 years
Impressive data shared by Ryan Potts @Amgen about how they QUALITY check previously unused E3 ligases for #PROTAC applications. Clearly showing how many more ligase are still out there to be highjacked for degrading disease causing proteins. @Undruggable #TPD21
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
How to get to orally efficacious VHL-based #PROTACs ? Redesign your target binder for optimal potency & permeability, make your degrader fast & efficient, strategically place a methyl to collapse the double-headed beast @alessiociulli @Boehringer @ChemRxiv
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
What a 10 minutes #Ras session opening lecture by @kevansf at #AACR22 ! Targeting #KRasG12S with lactone warheads providing a first set of cellularly active & selective probes. Another door in Ras targeting now opened.
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@HartungIngo
Ingo Hartung
@HartungIngo
3 years
Here we go again. After supposedly having had the potential to cure pancreatic cancer and Alzheimer’s disease (it didn’t), masitinib now becomes the new wonder drug to treat Covid patients. My recommendation: google “Shoichet”, “Science mag” and “phospholipidosis”...
@ScienceMagazine
Science Magazine
@ScienceMagazine
3 years
A repurposing screen identified the orally available drug masitinib as a broad antiviral that inhibits the main proteases of corona- and picornaviruses, and that effectively reduced #SARSCoV2 replication in mice. @UChicago
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
Input needed for a lecture/perspective paper: what are the most important approved or advanced clinical stage beyond-Rule-of-5 oral drugs? With respect to clinical impact or overcome discovery challenges. @Dereklowe @D_B_McConnell @drughuntersite @med_chemist
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@HartungIngo
Ingo Hartung
@HartungIngo
1 year
An excellent perspective by authors from @AstraZeneca about fragment-based approaches to identify ligands for E3 ligases. Of especially high relevance for the field of targeted protein degradation ( #TPD ). @ACSBioMed
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@HartungIngo
Ingo Hartung
@HartungIngo
3 years
A small molecule on the cover of Science! What a Christmas present. Plus it’s not often that I know the first author (Dafydd Owen) and can say that it’s so deserving to see this success. A great & humble scientist. Drug discovery at its best.
@JakeYeston
Jake Yeston
@JakeYeston
3 years
We don’t often put small molecules on the cover of @ScienceMagazine but the paxlovid development story (handled with inspiring acumen by @ValdaVinson ) is medchem at its sterling best. Congrats and thanks to the whole Pfizer team on their exceptional work!
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
Targeted protein degradation (TPD) continues to be the area of drug discovery research with the highest innovation speed. Pharma-Biotech partnerships are more and more at the core of this innovation. Especially for addressing some of the emerging #TPD challenges. @merckgroup
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@HartungIngo
Ingo Hartung
@HartungIngo
1 year
The sky is the limit for NCE drug discovery: Jim Cregg (Revolution Medicines) finally raising the curtain for #KRasG12C (On) tricomplex covalent inhibitor #RMC6291 at #AACR23 . „Simple is the new stupid“ (Barry M. Trost). My hat is off for this masterpiece of medicinal chemistry🥇
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
One impressive aspect of the @genentech study about directly hijacking the 26S proteasome for targeted protein degradation, is the way the PSMD2 ligand was identified. Here is the pioneering study about mRNA display selection back from 2001: #TPD #PROTACs
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@HartungIngo
Ingo Hartung
@HartungIngo
1 year
Difference between academia and industry: academic colleagues see picture and start telling stories about when they brought their young ones to the lab. Industry guy sees picture and wants to invite everybody to an ad hoc lab safety training.
@jjanetzko
John Janetzko
@jjanetzko
1 year
They said start em young, but so far this guy is not giving me anything helpful in the lab #dadademia
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@HartungIngo
Ingo Hartung
@HartungIngo
4 years
Another exceptionally helpful compilation from the Njardarson lab: beyond-Rule-of-5 oral drugs. . The top spots dominated by natural product-derived drugs & antivirals. The first fully synthetic non-antiviral on place 14: Bcl2 inhibitor venetoclax.
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@HartungIngo
Ingo Hartung
@HartungIngo
3 years
Targeted Protein Degradation (TPD) is changing the way how we think about small molecules in drug discovery. The first rationally designed degraders have reached clinical studies. By the end of 2021 I will not be able to still fit them on one slide. #TPDEurope @HansonWade
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@HartungIngo
Ingo Hartung
@HartungIngo
3 years
Now online: „No shortcuts to SARS-CoV-2 antivirals.“ How scientific diligence is a prerequisite to identify high quality antiviral drug candidates. Written together with the one and only @aledmedwards . @ScienceMagazine
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@HartungIngo
Ingo Hartung
@HartungIngo
3 years
Small molecule drug discovery was never more exciting than today. And medicinal chemistry is were the real fun happens. We now have two openings in our MedChem department in Germany: . Join our team of drug hunters @merckgroup .
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@HartungIngo
Ingo Hartung
@HartungIngo
5 years
Happy Thanksgiving, #PROTAC -aficionados! How to achieve in vivo efficacy with a picomolar degrader which has no oral bioavailability & zero solubility? Introducing PROTAC-ADCs. So far hidden in a 2017 patent @genentech , now out in @ChemMedChem . Exciting!
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
One of the remaining fundamental questions in targeted protein degradation space: what is the physiological function of Cereblon. The curtain starts to rise: The E3 ligase adapter cereblon targets the C-terminal cyclic imide degron | Nature
The E3 ligase adapter cereblon targets the C-terminal cyclic imide degron

Nature - C-terminal cyclic imides are physiological degrons that enable the ubiquitin E3 ligase adapter protein cereblon to target substrates for degradation.

www.nature.com
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@HartungIngo
Ingo Hartung
@HartungIngo
5 years
A new case study about deep learning in drug discovery @NatureBiotech : in 7 weeks to potent, cell active & lead-like DDR1 inhibitors: . Caveat: Using AI for such a target is like using Google Maps for locating Times Square. But you need to start somewhere.
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@HartungIngo
Ingo Hartung
@HartungIngo
4 months
Gwenn Hansen @Nurix_Tx about their experience how to achieve CNS penetration with #PROTACs : supporting the now well accepted view that molecular weight is not what MedChems should lose sleep about & that in vivo PK screening is still required to identify CNS penetrant degraders.
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
Another high impact study from the @DanNomura & @NovartisScience power-duo: Combining covalent fragment screening with the neddylation-on/off approach @georg_e_winter & @CrisMayorRuiz provides an UBE2D-highjacking NF-kB glue degrader: @biorxivpreprint #TPD
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@HartungIngo
Ingo Hartung
@HartungIngo
6 years
So many beautiful new small molecule drugs approved in 2018. Can somebody call all those business consultants who keep reiterating that the future of drug discovery is all about cell & gene therapies... @cenmag @lisamjarvis
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@HartungIngo
Ingo Hartung
@HartungIngo
1 year
Lots of stuff on my #AACR23 agenda. But what I am looking forward to the most is updating the chart below with two newly disclosed clinical stage #PROTACs : 2nd generation #AR degrader #ARV766 & #BRafV600E first-in-class degrader #CFT1946 . I keep waiting for @KymeraTx though. #TPD
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
In my opinion Carolyn Bertozzi deserves this prize twice. For her scientific contributions which are already more than enough to get the Nobel Prize. But as much for her being a role model for a cultural change in the academic chemistry community.
@NobelPrize
The Nobel Prize
@NobelPrize
2 years
Carolyn Bertozzi – awarded the 2022 #NobelPrize in Chemistry – has taken click chemistry to a new dimension and started utilising it in living organisms. Her bioorthogonal reactions take place without disrupting the normal chemistry of the cell.
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@HartungIngo
Ingo Hartung
@HartungIngo
4 years
This brings me back to the days of my own PhD thesis: Such an innocent looking macrodiolide, but the devil is lurking in the details. Impressive SAR studies by the Nicolaou group led by Johannes Krieger (now in MedChem @MerckHealthcare 💪). @J_A_C_S
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
Ubiquitin transfer is the so far least studied step in targeted protein degradation. In a new study by @Amgen & @promega modelling of the whole E3-PoI-E2-Ub assembly allows to rationalize relative degradation efficiency & to predict ubiquitination sites
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@HartungIngo
Ingo Hartung
@HartungIngo
4 months
Fantastic talk by Elisia Villemure @genentech on how to turn BRM/BRG (SMARCA2/4) bromodomain inhibitors into monovalent degraders by generating & screening a small library of derivatives. This time it’s not DCAF16 doing the job but E3 ligase FBXO22 (CRL1 complex) #AACR24 #TPD
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@HartungIngo
Ingo Hartung
@HartungIngo
1 year
#KRasG12C drug discovery case studies never get boring - even if you have heard the story before. So many nice vignettes of great drug hunter work which went into bringing #sotorasib into clinical studies & ultimately onto the market. Thanks to Brian Lanman @Amgen @GDCh_aktuell
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@HartungIngo
Ingo Hartung
@HartungIngo
1 year
Chemical #probes are important tools for validating drug targets. Covalent inhibitors & molecular degraders are expanding the druggable space. We now propose quality criteria for covalent & degrader probes: @ACSBioMed @Chemical_probes @thesgconline #TPD
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@HartungIngo
Ingo Hartung
@HartungIngo
3 years
Twitter-mediated experimental peer review of the not-so-Pd-free #Suzuki -Miyaura coupling recently reported in @NatureCatalysis . A shout out to @bedcatalysis and partners @BristolChem @pavel_kulyabin @durham_uni @ChemRxiv
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Ingo Hartung
@HartungIngo
1 year
Very cool: our perspective on quality criteria for covalent and degrader chemical probes is today‘s ACS Editors‘ Choice! This also means the article will be open access for the next 6 months! @ACSBioMed @AACR @thesgconline @Chemical_probes
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@HartungIngo
Ingo Hartung
@HartungIngo
4 years
#PROTACs are sometimes described as double-headed beasts (giving drug hunters PK-headaches). Turns out they are chameleons. Or they should better be designed that way to achieve high passive permeability & cell activity. @DuyNguyen_Bayer @ACSBioMed
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@HartungIngo
Ingo Hartung
@HartungIngo
1 year
Progress in targeted protein degradation ( #TPD ) is limited by a scarcity of know-how about human E3s. High quality chemical probes can help to bridge that gap as now exemplified for #GID4 by scientists @pfizer & @thesgconline #OpenScience @biorxivpreprint
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@HartungIngo
Ingo Hartung
@HartungIngo
3 years
The plot thickens regarding the structure of IRAK4 PROTAC KT-474 @KymeraTx . 2 patents disclosing deuterated, crystalline & salt forms of a single PROTAC. Comprising a non-conventional CRBN binder the chemists at Kymera seem to like a lot. More common NH-linked IMiD in KT-413?
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@HartungIngo
Ingo Hartung
@HartungIngo
5 years
A new poster from Jón Njardarson’s group @UAresearch : Top 200 Small Molecules in 2018. Diverse flavors of #SMOLs represented by 2 reversible FXa inhibitors, a glue and an irreversible BTK inhibitor leading the pack. But also surprising simplicity in Top10
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@HartungIngo
Ingo Hartung
@HartungIngo
3 years
The #PROTAC community will be sitting in front of their computers on April 11th 2 pm EST. In back-to-back presentations @ArvinasInc will disclose the chemical structures of #ARV110 & #ARV471 along with a clinical update. Let's see who got both of them right. @AACR #AACR2021
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@HartungIngo
Ingo Hartung
@HartungIngo
1 year
Certain MEK inhibitors induce a complex between #MEK & difficult-to-degrade #cRAF . This allows bystander degradation of recalcitrant cRAF w/ #PROTACs targeting MEK. Excellent study by the Duncan & Jin labs @FoxChaseCancer @IcahnMountSinai @biorxivpreprint
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
I have only now realized that the structure of FHD-609 has been disclosed @foghorntx . A dual BRD7/9 bromodomain binder, a H bond donor-free spirocylic linker & a lenalidomide-type CRBN engager provide a BRD9-selective #PROTAC free of molecular glue activity. Dosed iv in Ph1.
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@HartungIngo
Ingo Hartung
@HartungIngo
4 months
AR-PROTAC BMS-986365 is a potent & rapid AR degrader with enzalutamide-like antagonist potency, low AR agonism, weak activity against AR L702H, claimed to be selective against CRBN neosubstrates (data not shown) & allows to overcome AR feedback up-regulation. #AACR24 #TPD
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@HartungIngo
Ingo Hartung
@HartungIngo
4 months
Introducing ARV-393: an ultra-potent & rapid #PROTAC degrader of BCL6 with consistent PK properties across species. Of note, a PROTAC with an occupancy-drug-like PK profile to overcome fast protein synthesis rebound. Neosubstrate selectivity: “clean enough to progress” #AACR24
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@HartungIngo
Ingo Hartung
@HartungIngo
1 year
Takeyuki Nagashima @AstellasUS was tight-lipped (understandably) when asked for more details about #KRasG12D degrader #ASP3082 . The data he shared were still highly interesting & form a milestone in therapeutically targeting yet another #KRas oncogene. #AACR23 #TPD #PROTACs
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@HartungIngo
Ingo Hartung
@HartungIngo
9 months
Strong data set disclosed by Steven Sparks @ArvinasInc at #TPD23 showing degradation of brain #LRRK2 by an orally dosed #PROTAC in non-human primates. Another frontier in the #TPD space about to be overcome! Disease-causing proteins in neurological diseases now in scope!
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@HartungIngo
Ingo Hartung
@HartungIngo
3 years
Impressive talk by Norbert Kraut @Boehringer at #AACR21 showcasing their multi-pronged approach to tackle the different oncogene versions of #KRas . The power of collaborations between bright minds & as a special treat the first X-Ray for a KRas-PROTAC ternary complex (VHL)
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
To increase productivity, you need to speed up your slowest process step. In drug discovery identifying hits is such a bottleneck. Chemical Space Docking may provide an efficient way to screen vast chemical spaces in silico. #AIDD @genentech @biosolveit
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
This is an excellent graphic @CrisMayorRuiz summarizing approaches for the identification of molecular glue degraders: from completely serendipitous to target & ligase focused (including VHL examples only shown so far at conferences). @ChemSocRev #TPD
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@HartungIngo
Ingo Hartung
@HartungIngo
4 months
My colleague @MarcelRieker2 @merckgroup about bringing together two exciting areas of drug discovery: protein degraders & antibody-drug conjugates. Delivering degraders to diseased cells in (very) complicated ways and in potentially more simple ones. #TPD #ADC #AACR24
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@HartungIngo
Ingo Hartung
@HartungIngo
3 months
The last scientific symposium at #AACR24 opened by @pottslab with a highly educational talk about non-degrading molecular glues targeting #KIF18a or #PRMT5 . Shifting the drug discovery paradigm towards reducing metabolite/protein-protein interaction off-rates to block function.
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@HartungIngo
Ingo Hartung
@HartungIngo
1 year
One of my must-read papers in J. Med. Chem. @ACSBioMed is the annual compilation of fragment-to-lead cases. The 2021 edition comprises 28 entries, several for difficult-to-drug targets. For kinases fragments can provide an entry into structure-based design
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@HartungIngo
Ingo Hartung
@HartungIngo
3 years
Impressive presentation by Chris de Savi @Kymera at today's ligase targeting conference @Undruggable . Outlining how they systematically select novel E3s for #PROTACs & allowing first glimpses at binder identification & PROTAC validation work for an untouched Cullin Ring E3 ligase
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@HartungIngo
Ingo Hartung
@HartungIngo
3 years
Innovation speed in the field of targeted protein degradation is still increasing. Soon the chemical structures of the most advanced #PROTACs in clinical development will be disclosed. And the next wave of innovation has already hit the shore... #TPDEurope #AACR2021
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@HartungIngo
Ingo Hartung
@HartungIngo
3 years
It's now >6 months since concerns were raised about the "amine-free Suzuki coupling" published in @NatureCatalysis . There is overwhelming evidence that the active catalyst is not the free amine but rather a Pd impurity. How much more time will it take to clean up the record?
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
With an increasing interest in targeted protein degradation, more studies about efficient synthetic approaches to bifunctional degraders get published. Here is an elegant example for the use of multi-component Ugi/Passerini couplings @ChemRxiv #PROTACs
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@HartungIngo
Ingo Hartung
@HartungIngo
3 years
I like the summary in a most recent highlight on structure-based design of degrader molecules: "We will need to be patient, solve one ternary complex structure at a time, keep studying & learning". A perfect #TPD motto for 2022 @PhilippMCromm @laura_m_luh
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@HartungIngo
Ingo Hartung
@HartungIngo
1 year
Updated overview of disclosed clinical stage #PROTACs + educated guesses. Of note the growing chemical diversity of #CRBN binders. Convincing selectivity data shown for ARV-766 against IMiD targets IKZF1/3, GSPT1, SALL4. An emerging path into non-oncology indications #TPD #AACR23
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@HartungIngo
Ingo Hartung
@HartungIngo
5 years
Synthetic routes for drugs approved in 2017 @JMedChem . A useful reference for chemistry students interested in learning about modern day medicinal chemistry synthesis challenges. May even help to get you through a job interview... @Total_Synthesis
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
Entropy favors the preorganized one: YAP-TEAD4 protein-protein interaction disruptors by @NovartisScience . Being frozen in its bioactive conformation allows custom-built SMOLs to compete off much larger, intrinsically disordered peptides @ChemMedChem
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@HartungIngo
Ingo Hartung
@HartungIngo
3 years
It’s always a special treat to hear @jaybradner talk about targeting the undruggable: about intermolecular #VHL glues, intramolecular splicing modulators & potentiators of #KRas -targeted drugs: Dana-Farber Targeted Degradation Webinar Series via @YouTube
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@HartungIngo
Ingo Hartung
@HartungIngo
5 years
MacroPROTACs by @alessiociulli @EndriuT @xlucas_basel : previously on @ChemRxiv , now online @angew_chem . Freezing conformational flexibility provides an additional level of degradation selectivity. Structure-based design of #PROTACs is becoming a reality.
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@HartungIngo
Ingo Hartung
@HartungIngo
4 years
Total synthesis of natural products is THE training ground for next generation medicinal chemists: it requires holistic thinking, perseverance & creativity to overcome so many hurdles. Exhibit 1: #Taxol @BaranLabReads @ChemRxiv . I hereby rest my case.
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
Here is a review about Degrader-ADCs written by Peter Dragovich @genentech . This review is an excellent read based on the significant hands-on experience of the author. And he does a superb job in explaining ADC basics to the lay reader @rsc_medchem #TPD
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
Important new review just published about the growing importance of small molecular drugs in boosting anti tumor immunity. Written by my colleagues at @merckgroup together with Rienk Offringa @DKFZ . @NatRevDrugDisc
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@HartungIngo
Ingo Hartung
@HartungIngo
1 year
Not only the quality of a chemical probe decides about the robustness of generated cell biology data. Low quality experimental design will undermine the quality of any reagent. And this seems to be the reality - as this sobering study shows. @NatureComms
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@HartungIngo
Ingo Hartung
@HartungIngo
6 months
The list of high-quality molecular glue degrader probes is growing with the recent addition of a VHL-CDO1 glue degrader (kudos @NovartisScience ). Now covering 4 E3 ligases (CRBN, VHL, DCAF15 & 16) and a homo-dimerization-degradation mechanism. #TPD
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@pottslab
Ryan Potts
@pottslab
6 months
New era in targeted protein degradation: A groundbreaking molecular glue selectively degrades proteins via the VHL E3 ligase, diverging from conventional CRBN glues. This discovery opens new avenues for #TPD .
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
Many of us have been noticed by @EnamineLtd about how the Russian invasion impacts their business & puts lives of their employees in Kyiv at risk. We all need to understand the significance of what is happening in Europe today. It's not a day for posting wordles or cat pictures.
@EnamineLtd
Enamine Ltd 🇺🇦
@EnamineLtd
2 years
Join series of webinars dedicated to Enamine’s 30th Anniversary Overview of Enamine’s Scientific Achievements Overview of Enamine’s Compound Libraries The Role of Enamine in the Era of Digital Pharmacology
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@HartungIngo
Ingo Hartung
@HartungIngo
5 years
First human PK data for a #PROTAC now available @ArvinasInc : AR degrader ARV-110 shows very long human half-life leading to significant accumulation upon daily oral dosing; total plasma exposure & Cmax at day 15 reach levels of efficacious doses in mice.
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
An underrated success factor in Pharma drug discovery is the ability to tap into the organization's wealth of knowledge. Here is an excellent perspective by medicinal chemists @Merck about their efforts to enable & stimulate knowledge sharing @ACSBioMed
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@HartungIngo
Ingo Hartung
@HartungIngo
9 months
It was a proud moment yesterday when my colleague Marcel Rieker disclosed our #PROxAb shuttle technology at #TPD23 @Undruggable . Along with the poster by Hendrik Schneider they outlined our plug-and-play platform for delivering VHL-based #PROTACs to diseased cells. @merckgroup
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
The curtain seems to rise & allow a glimpse at Ph1 IRAK4imid @KymeraTx KT-413: use patent for a triple #PROTAC degrader of IRAK4, IKZF1 & IKZF3; a NH-linked thalidomide warhead in line with emerging neosubstrate SAR; noteworthy intermittent dosing schedules & non-rodent PK data
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
@mathieuvonrohr Natürlich wird hier aktiv ein bestimmtes Image aufgebaut. Aber dieses Image ist authentisch. Ist mir - als jemand der die Grünen nicht wählt - lieber als DAX-Vorstände, die nach 20 Jahren die Krawatte weglassen, weil ihnen gesagt wurde, das sie so dynamischer wirken…
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@HartungIngo
Ingo Hartung
@HartungIngo
4 years
The known unknowns of designing #PROTACs exemplified on one slide: #KRas (G12C) can be degraded in cancer cells if the target binder-linker-E3 puzzle is solved the correct way. The result may even overcome ERK pathway reactivation! @ChemRxiv @CraigMCrews
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@HartungIngo
Ingo Hartung
@HartungIngo
4 years
With Joe in office, time to focus back on science: Introducing RNA-PROTACs courtesy of the Hall group @angew_chem : first proof of cellular principle & potentially a nice complementation of #TRAFTACs . Though early days with respect to degradation efficacy.
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@HartungIngo
Ingo Hartung
@HartungIngo
4 years
The FDA approval of #EZH2 inhibitor #tazemetostat is a milestone for epigentic drug discovery (despite the controversy about its clinical value). EZH2 inhibitor design is also a poster child for the value of optimizing conformations @JMedChem @EpizymeRx @CPI_epigenetics @pfizer
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@HartungIngo
Ingo Hartung
@HartungIngo
5 years
IMHO the best research paper in 2019: @Amgen disclosing the pharmacological profile of #KRas inhibitor #AMG510 . So much intriguing science compressed into 7 pages. State-of-the-art profiling of a covalent inhibitor & a focus on clinical translation @nature
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@HartungIngo
Ingo Hartung
@HartungIngo
1 year
Understanding clinical needs & translating into a drug target profile is the basis for impactful drug discovery. It takes an exceptional team to fulfill such a profile. Proud about the M4205/IDRX-42 discovery team @merckgroup (now in Ph1). @ACSBioMed
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
Our dear Heavenly Father, we thank thee for the daily protein degradation review…
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@HartungIngo
Ingo Hartung
@HartungIngo
2 years
Translational bed-to-bench research for targeted protein degraders will soon pick up speed. This important study by @alessiociulli & @georg_e_winter identifies VHL & CRBN hotspots for degrader sensitivity (via ternary complex modulation): @biorxivpreprint
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