MedChemCASES: Online-Seminare der GDCh-Fachgruppe Medizinische Chemie

MedChemCASES ist eine im Jahr 2020 gestartete Online-Seminarreihe der GDCh-Fachgruppe Medizinische Chemie, in deren Rahmen Fallstudien aus Industrie und akademischer Forschungslandschaft präsentiert werden. Das Programm wird konzipiert in Zusammenarbeit mit der Gruppe NextGenMedChem.

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MedChemCASES #15: Dr. Tim Owens

Dr. Tim Owens (Principia - Sanofi)
May 24, 2022
5:00 PM (Berlin time)  

Registration link:

Development of Reversible Covalent Inhibitors as Chemical Probes and Clinical Candidates
In  2013, Serafimova  assessed  a  series  of  electrophilic  molecules  that  engaged  non-catalytic  cysteines  in  a  covalent  manner, but  with  variable  target  residence  times, driven by the various stabilizing interactions of the molecule in the protein binding site. These reversible covalent inhibitors were shown to rapidly dissociate from common thiols while maintaining sustained inhibition of a target protein even after washout. This technology, therefore, has the potential to allow medicinal chemists to fashion inhibitors with  the  potential  for  selectivity gained  by  inhibiting  only  targets  with  a  conserved cysteine, and  minimal  exposure  requirements  inherent  with  covalent  inhibition.  The reversible  covalent  approach  furthermore mitigates  risk  of  irreversible  binding  to  non-target  cysteines  or  endogenous  thiols,  but  also  allows  the  potential  to  improve selectivity among targets sharing a common cysteine. This technology has been used to identify selective inhibitors of kinases such as BTK and FGFR as well as LMP7 subunit of the immunoproteasome. Based on our interest in BTK inhibition for the treatment of immune mediated disorders, we embarked on  a drug  development  effort  to  identify  reversible  covalent  inhibitors  culminating  in  the identification of PRN473 for topical administration and PRN1008 (rilzabrutinib) as an oral BTK inhibitor currently in multiple phase 3 studies.

MedChemCASES #14: Dr. David Battersby

Dr. David Battersby (GSK)
April 28, 2022
5:00 PM (Berlin time)  

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High-throughput PROTAC synthesis for direct, biological assaying
Direct-to-biology (D2B) synthesis and assaying has the potential to cut drug-discovery cycle times by providing information rich experiments in a highly efficient manner. For PROTACs, this cycle time is often slower than conventional medicinal chemistry as there are a plethora of small molecule E3-ligase or protein-of-interest binders and vectors to investigate as well as a vast landscape of linker chemical space to explore; finding the optimum for these three individual components is time-consuming and resource intensive. An attractive alternative would be to conduct miniaturized reactions in 1536-well plates, where all three PROTAC components are simultaneously evaluated, and directly assessed as crude reactions in cell-based HiBiT assays. Judicious reagents choice is required to ensure high reaction conversion and, moreover, minimize any effect on cell-viability. This talk will showcase our Direct-to-biology protocol to assess crude PROTACs using two well established PROTAC target case-studies: HER2 and BRD4.

MedChemCASES #13: Dr. David Thaisrivongs

Dr. David Thaisrivongs (MSD)
February 23, 2022
5:00 PM (Berlin time)  

Registration link: 

Synthetic macrocyclic peptides that target protein-protein interactions: the discovery and early chemistry development of a PCSK9 inhibitor
Inhibition of Proprotein Convertase Subtilisin/Kexin type-9 (PCSK9) improves cardiovascular outcomes in patients requiring additional low-density lipoprotein cholesterol reduction on top of statins, but there has been limited uptake of the two commercialized PCSK9 antibody inhibitors due in part to cost and route of administration. The protein-protein interaction between PCSK9 and the low-density lipoprotein receptor which is targeted by these therapies is a large, flat surface, which has made the discovery of orally-bioavailable small molecule inhibitors highly challenging. This talk will introduce the use of macrocyclic peptides to interrupt such protein-protein interactions, and describe the discovery and early chemistry development of such a PCSK9 inhibitor.

MedChemCASES #12: Dr. Jörg Kley

Dr. Jörg Kley (Boehringer Ingelheim)  
January 26, 2022
5:00 PM (Berlin time)  

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Discovery of BI 1265162, an ENaC Inhibitor for the Treatment of Cystic Fibrosis 
BI 1265162 is an inhaled epithelial sodium channel (ENaC) inhibitor that reached clinical phase 2. This talk will discuss different approaches to achieve lung tissue selective ENaC inhibition and present how the structure of BI 1265162 evolved from a literature starting point. Besides the need for a long duration of action without renal side effects, physicochemical properties required for administration via the Respimat® Soft Mist™ inhaler guided our compound optimization.BI 1265162 contains a phosphine oxide moiety, and the properties brought in by this less common structural element are discussed.

MedChemCASES #11: Keith Graham

Dr. Keith Graham (Bayer)
November 18, 2021
4:00 pm (Berlin time)

Joint event with the EFMC-YSN, followed by a round table discussion
“Life as a foreign scientists in Germany”.

The seminar is free of charge, but REGISTRATION is needed.

Discovery of potent SOS1 inhibitors and their pharmacological investigations to disrupt the RAS-SOS1 interaction​
Mutants of RAS are major oncogenes and are prevalent in many human cancers, however efforts to develop drugs that directly inhibit the corresponding constitutively active RAS proteins have been unsuccessful so far, although there are promising new findings for KRas-G12C covalent inhibitors. We focused on SOS1, the guanine nucleotide exchange factor (GEF), and an activator of RAS. We identified good starting points for medicinal chemistry activities using both high-throughput and fragment screens. Initial optimizations resulted in the discovery of the first nanomolar SOS1 inhibitors, which effectively downregulated active RAS in tumour cells. Here, the key findings on our path to identifying novel potent and cellular active small molecule inhibitors will be described. These inhibitors efficiently disrupted the interaction between KRAS and its exchange factor SOS1, this mode of action was confirmed by a series of biophysical techniques. The binding sites, mode of action and selectivity were elucidated using crystal structures of KRASG12C–SOS1, SOS1 and SOS2. By preventing formation of the KRAS–SOS1 complex, these inhibitors block the reloading of KRAS with GTP and, therefore, showed antiproliferative activity. Our probe BAY-293 selectively inhibited the KRAS–SOS1 interaction with an IC50 of 21 nM and is a valuable chemical probe for further investigations. In cells with wild-type KRAS the complete inhibition of the RAS–RAF–MEK–ERK pathway was observed. In a mutant KRAS cell line, SOS1 inhibition resulted in a reduction of pERK activity by 50%. Together, the data indicate that inhibition of GEFs may represent a new viable approach for targeting RAS-driven tumours.


MedChemCASES #10: Stephen Fesik

Name: Stephen Fesik (Vanderbilt University School of Medicine, Nashville, TN, USA) 
Date: October 21, 2021, 4:00 pm 
Chairs: Chistian Kuttruff, Julien Lefranc 
Co-Chair: Franz von Nussbaum

Title: The Discovery of Potent WDR5 Inhibitors for the Treatment of Cancer
WDR5 is a component of multiple epigenetic regulatory complexes, including the mixed lineage leukemia (MLL)/SET complexes that deposit histone H3 lysine 4 methylation. Overexpression of WDR5 correlates with a poor clinical outcome in many human cancers, and WDR5 has emerged as an attractive target for therapy. We discovered potent WDR5 inhibitors using fragment-based methods and structure-based design. These inhibitors have been optimized for their drug-like properties and show potent oral activity in tumor xenograft mouse models. They act not by altering histone methylation but by displacing WDR5 from chromatin at protein synthesis genes, choking the translational capacity of these cells, and inducing death via a nucleolar stress response. Our inhibitors could thus have broad therapeutic utility as anti-cancer agents.

MedChemCASES #9: Timo Heinrich

Name: Timo Heinrich (Merck KGaA, Darmstadt) 
Date : September 23, 2021, 4:00 pm 
Registration link 

Chair: Tatjana Ross, Franca Klingler 
Co-Chair: Franz von Nussbaum 

Title: Discovery and Optimization of Next Generation Reversible Methionine Aminopeptidase-2 Inhibitors – Identification of clinical compound M8891 
Co- and post-translational protein processing is important to ensure the maturation to functional proteins. MetAP-2 proteolytically removes the amino-terminal methionine from nascent proteins, and inhibition of its activity has been shown to block angiogenesis and tumor growth, suggesting that small-molecule inhibitors of MetAP-2 may be promising options for the treatment of cancer. This talk describes how 
persistence and serendipity helped to identify a previously unknown MetAP-2 inhibitory scaffold. The biochemical activity of more conventional, purine base compounds did not translate to cellular activity. Thorough analysis of HTS screening results led to the identification of chiral tartronic diamide hits. Structure-based hit-to-lead optimization is out-lined, including different synthetic strategies for most efficient access to improved derivatives as well as asymmetric approaches. The initial lead compound suffered from enterohepatic circulation, preventing further development. Binding kinetics were investigated by fluorescence cross correlation spectroscopy and residence time on the target protein was one important characterization criterion. Adjustment of H-bond donor/acceptor count and multiparameter analysis of the compound properties led to the nomination of the clinical development compound M8891, which impedes the growth of primary endothelial cells, shows dose-dependent biomarker modulation and antitumoral activity in mouse xenograft models. 

MedChemCASES #8: Stefan Knapp

Stefan Knapp (Universität Frankfurt)
June 24, 2021
4:00 pm (Berlin time)

Chairs: Matthias Gehringer, Eleonora Diamanti
Co-Chair: Franz von Nussbaum

Title: Targeting protein scaffolding function in kinases 
In living cells, protein kinases are organized in large signalling complexes comprising adapter proteins, diverse enzymes and regulatory proteins. In recent years it has become increasingly evident, that protein kinases act not only as independent enzymes but that they also function as protein interaction scaffolds organizing the assembly of signalling complexes in a conformation sensitive way. This complexity is also reflected by the response of kinases to inhibitors that may stabilize diverse conformations acting as inhibitors of enzymatic activity only, as modulators of kinase scaffolding roles or both. In this talk, I will exemplify the implications of altering protein interactions by allosteric small molecules as well as canonical ATP competitive inhibitors using a number of selective inhibitors that we developed recently. I will demonstrate how different binding modes that alter protein conformation and dynamics in a distinct way may result in diverse signalling outcomes and phenotypic responses. The important scaffolding roles of protein kinases will also enable targeting new and so far poorly explored members of the kinase family such as catalytically inactive pseudokinases, that represent a considerable number of largely unexplored kinase targets which have been linked to the development of many diseases.  


MedChemCASES #7: Cristina Nevado

Postponed due to unforeseen events. The webinar will be rescheduled at a later date. We apologize for any inconvenience.

Cristina Nevado (University of Zurich, Switzerland) 
Chairs: María Méndez Pérez, Franca Klingler 
Co-Chair: Franz von Nussbaum 

"Exploring the chemistry and biology of CREBBP and EP300 Bromodomains"
Expanding the chemical space and simultaneously ensuring synthetic accessibility is of upmost importance, not only for the discovery of effective binders for novel protein classes but, more importantly, for the development of compounds against hard-to-drug proteins. In this talk we will introduce AutoCouple, a de novo approach to computational ligand design focused on the diversity-oriented generation of chemical entities via virtual couplings. In a benchmark application, chemically diverse compounds with low-nanomolar potency for the CBP bromodomain and high selectivity against the BRD4(1) bromodomain were achieved by the synthesis of about 50 derivatives of the original fragment. The binding mode was confirmed by X-ray crystallography, target engagement in cells was demonstrated, and antiproliferative activity was showcased in three cancer cell lines. 

MedChemCASES #6: Jun Liang

Jun Liang (Genentech, USA)
April 1, 2021
4:00 pm (Berlin time)
Franca Klingler, Julien Lefranc
Co-Chair: Franz von Nussbaum

"Discovery of a highly potent and orally bioavailable Selective Estrogen Receptor Degrader (SERD) GDC-9545 for ER-positive breast cancer"
Breast cancer is the most common cancer and second leading cause of cancer death in women. Approximately 70% of breast cancers are ER-positive (ER+). Standard of care therapies include Selective Estrogen Receptor Modulators (SERMs), such as tamoxifen, and aromatase inhibitors. Despite their initial effectiveness, 20-30% of patients eventually relapse, and become resistant due to ER mutations. Fulvestrant, a full antagonist of ER and later found to be a SERD, was approved to treat advanced and metastatic disease. However, fulvestrant is not orally bioavailable and needs to be injected intramuscularly due to its unique pharmacokinetic and pharmaceutical properties. We were attracted by the dual mechanisms of fulvestrant: a full antagonist and an SERD. Herein we report the discovery of GDC-9545, a highly potent full antagonist and orally bioavailable SERD with improved pharmacokinetic and pharmaceutical properties, guided by structure- and property-based designs. In vitro, GDC-9545 showed excellent antagonist potency and consistent ER degradation across ER+ cell lines. In vivo, GDC-9545 demonstrated dose-dependent efficacy in both ER wild-type and mutant xenograft models, achieving tumor regression at 1/100th dose of GDC-0927. Moreover, GDC-9545 did not exhibit partial agonist effect in the uterus of immature rats, and was well tolerated in pilot tox studies. In humans, GDC-9545 showed excellent PK profiles and is currently in Phase III clinical trials.  

MedChemCASES #5: Michiel Van Gool

Michiel Van Gool (Janssen R&D, Spain)
January 21, 2021
4:00 pm (Berlin time)
Julien Lefranc, María Méndez Pérez
Co-Chair: Franz von Nussbaum

"The design of mGlu2 NAMs for neuropsychiatric disorders and tracers for PET imaging"
Glutamate, the main excitatory neurotransmitter in the brain, acts on two distinct classes of receptors: the ionotropic (NMDA, AMPA, Kainate) and metabotropic glutamate (mGlu) receptors. The mGlu receptors play an important modulatory role in neurotransmission and are closely involved in a variety of physiological functions. Preclinical data support the therapeutic potential of negative allosteric modulation of the mGlu2 receptor in neuropsychiatric disorders such as depression and improvement in cognitive function in disorders like Alzheimer Disease. A high throughput screening (HTS) campaign resulted in an attractive pyrazole hit with moderate potency as negative allosteric modulator of the mGlu2 receptor. A focused medicinal chemistry optimization effort led to a lead compound with single digit nanomolar potency.1 Further evaluation of this lead, focused on reducing lipophilicity by means of a drastic change in the central scaffold, led to a pyrazolo-dihydropyrazinone bicycle with improved drug-like properties. Further optimization towards the ideal substitution pattern resulted in the selection of a candidate for clinical evaluation. In parallel to our Medicinal Chemistry efforts, we started a research program to discover an mGlu2 NAM-based PET radiotracer for in vivo imaging of this receptor in brain, applying our reported strategy.2 Several differently substituted derivatives framed within the pyrazolo-dihydropyrazinone bicycle were synthesized, containing motifs that could be eventually radiolabeled either with 11C or 18F. We will present the synthesis and biological evaluation of a set of compounds belonging to this new series of mGlu2 NAMs, and assessment as potential PET ligands of the most promising candidates.

MedChemCASES #4: Darryl B. McConnell

Darryl B. McConnell, PhD (Boehringer Ingelheim Regional Centre Vienna, Austria)
December 3, 2020

4:00 p.m. (Berlin time)
Christian Kutruff, María Méndez Pérez
Co-Chair: Franz von Nussbaum

"Drugging the Top 9 KRAS Mutants"
KRAS drives 1 in 7 of all human cancers. 90% of the KRAS driven cancers are caused by 9 different KRAS mutants. It took 36 years to bring drugs against the first KRAS mutant KRASG12C to Phase 1 clinical trials after Channing Der’s discovery in 1982 that KRAS is an oncogene. It will be discussed why it took so long for medicinal chemists to discover drugs against the first KRAS mutant and BI’s learnings from internal efforts against KRAS. Importantly, it will be highlighted what this means for the future practice of medicinal chemistry (MedChem2.0). The talk will also highlight a selection of the multiple approaches that Boehringer-Ingelheim is taking to drug KRAS including pan-KRAS concepts and selective KRAS concepts. The importance of not only inhibiting MAPK pathway signaling but also blocking negative feedback will be emphasized. The practice of MedChem2.0 will be needed to drug the many KRAS mutants yet to be drugged in order to bring medicines to patients with KRAS driven cancers and RASopathies.

MedChemCASES #3 (Special Edition): Oliver Koch, Daniel Merk

Special Edition: Innovation Award 2020
October 28, 2020
4:00 p.m. (Berlin time)
Matthias Gehringer, Franca Klingler 
Co-Chair: Franz von Nussbaum

PD Dr. Oliver Koch (Westfälische Wilhelms-Universität Münster, Germany)
“The use of data-driven decisions for rational molecular design”

The increase in the number of protein structures and the enormous amounts of bioactivity data still require new approaches for efficient data mining and knowledge discovery. One focus of my research is (new) data-oriented methods and artificial intelligence for the analysis of protein-ligand interactions and the underlying framework of protein binding sites. The goal is to use this knowledge, the available "big" bioactivity data, and protein structures for computational molecular design and optimization of new bioactive compounds. In the first presented project, our analysis to identify a promiscuous fragment that can be used for fragment-based design approaches is discussed. This result was based on a scaffold analysis of bioactivity data and comparison of binding sites. The second project deals with domain-specific fingerprints generated by neural networks that improve ligand-based virtual screening.

PD Dr. Daniel Merk (Goethe University Frankfurt, Germany)
“Advances in targeting retinoid X receptors”

The nuclear retinoid X receptors (RXR) act as ligand-sensing transcription factors and hold great promise for neurodegeneration and cancer treatment. However, available RXR agonists exhibit severe adverse effects, have poor properties and lack subtype-selectivity hindering exploitation of this therapeutic potential. We have applied diverse strategies to overcome these obstacles in targeting RXRs. We have observed RXR modulation by several approved drugs, the systematic optimization of which produced potent RXR agonists with superior properties. In the search of subtype-preferential RXR ligands we hypothesized natural products (NP) as promising candidates and discovered valerenic acid as selective RXRβ agonist. Computational de novo design provided several NP-derived subtype-preferential RXR ligand scaffolds and revealed selectivity-driving structural features. Additionally, we have solved the first uniform set of RXR co-crystal structures in active conformation bound to an identical ligand as structural basis for selective RXR agonist design. Our results open avenues to new generations of RXR modulators. Obtaining subtype-selective RXR agonists remains a challenge, however.

The Innovation Award is jointly funded by the Division of Medicinal Chemistry of the German Chemical Society (GDCh) and the Division of Pharmaceutical/Medicinal Chemistry of the German Pharmaceutical Society (DPhG), to honor outstan-ding and independent scientific research of young scientists in the areas of medicinal and pharmaceutical chemistry.

MedChemCASES #2: Ed Tate

Prof. Dr. Ed Tate (Imperial College London and Francis Crick Institute)
September 2, 2020
4:00 p.m. (Berlin time)
Gerhard Hessler, Franz von Nussbaum
Co-Chair: Franca Klingler

“Targeting protein modification: from chemical biology to drug discovery” 
My group works on a wide range of chemical biology approaches focused primarily on small molecule probes that enable drug target identification and validation. Particularly active areas of research include conditional protein degradation, photoaffinity-driven target discovery, activity profiling of proteases and deubiquitinases, covalent fragment-based drug design, protein-protein interaction inhibitors, and chemical proteomic approaches to understand and target protein post-translational modifications. In this talk I will discuss our work in some of these areas, illustrated with examples of projects which have delivered small molecules into preclinical development.

MedChemCASES #1: Doyle Cassar

Dr. Doyle Cassar (Astra-Zeneca)
July 9, 2020
4:00 p.m. (Berlin time)

Chairs: Gerhard Hessler, Franz von Nussbaum
Co-Chair: Franca Klingler

“Allosteric Covalent Inhibitors of the Mutant GTPase KRASG12C” 
Of all human cancers, 20% have a mutation in GTPase KRAS with a high frequency being found in pancreatic, colorectal and non-small cell lung cancer (NSCLC).  A glycine to cysteine mutation at codon 12 is the most frequent mutation found in NSCLC, rendering KRAS constitutively active and driving cell proliferation, survival and differentiation. Covalent targeting of this cysteine residue offers the potential for selective inhibitors of the G12C mutant isoform and an allosteric mode of action potentially negates the impact of high nucleotide binding affinity for the GTPase. A knowledge- and structure-based design approach was utilised to derive diverse series of covalent inhibitors that interact directly with this cysteine mutation, causing a shift in the switch II region and rendering KRAS inactive. This talk will highlight our development of a series of candidates with excellent DMPK properties and superior efficacy to other agents targeting this mechanism.

zuletzt geändert am: 16.04.2021 17:08 Uhr von C.Kniep