KEAP1 inhibition/NRF2 activation has been hotly pursued in recent years for immunology indications; however, in oncology, NRF2 degradation has been posited as a novel therapeutic mechanism for specific cancers. Vividion has already disclosed work on covalent KEAP1 inhibitors, but at the recent ACS Fall 2024 meeting, the structure and discovery story of their clinical oral covalent activator of KEAP1 were disclosed, identified through careful analysis of the data from their inhibitor screen.

BridgeBio’s BBO-8520 is a selective, covalent KRAS(G12C) inhibitor which differentiates itself from the pack by engaging the (ON) state of the protein, potentially conferring increased clinical benefit in KRAS(G12C)-driven cancers, including overcoming resistance to current treatments. Disclosed at the 2024 AACR Annual Meeting in San Diego, is currently in a Ph. I trial in patients with advanced non-small-cell lung cancer. This article covers the structure, mechanism of action and preclinical efficacy that marks this compound out as one to watch.

RMC-9805 is a first-in-class, covalent KRAS(G12D)(ON) molecular glue inhibitor from Revolution Medicines that uses a cyclophilin A (CypA)-recruiting tricomplex mechanism combined with a finely tuned aziridine covalent handle to inhibit the previously “undruggable” KRAS(G12D) mutant. Read our coverage of the discovery story, disclosed at the AACR 2024 meeting in San Diego, to discover how structural and modeling insights were key to engaging a poorly nucleophilic mutant Asp, how RMC-9805 synergizes with PD-1 inhibitors, and the progress this remarkable compound is making in the clinic.

VVD-214/RO7589831 is an oral covalent, reversible, and allosteric inhibitor of WRN helicase discovered by the San Diego-based biotech Vividion Therapeutics and being developed by Roche for tumors marked by microsatellite instability and/or mismatch repair deficiency. Vividion has utilized its chemoproteomics platform to discover and develop novel treatment options for oncology targets. The structure and initial preclinical pharmacology data for VVD-214 were recently disclosed at the AACR Annual Meeting 2024 in San Diego. VVD-214 is currently being evaluated in a Ph. I trial.

Nrf2/KEAP1 modulation has been pursued since the discovery that dimethyl fumarate and its metabolite protect CNS neurons via up-regulation of Nrf2-depdendent activities. Compounds with greater selectivity have been sought for many years, culminating with the approval of the KEAP1 inhibitor, omaveloxolone. Vividion disclosed their efforts to identify the covalent KEAP1 inhibitor, VVD-702. This ACS Spring 2024 disclosure is an excellent case study for covalent hit finding using chemoproteomics, covalent compound optimization, and the use of an uncommon but surprisingly stable covalent warhead.

PF-07817883 (ibuzatrelvir) is an oral, second-generation SARS-CoV-2 M^pro inhibitor developed by Pfizer. These efforts follow the success of Pfizer's antiviral combination drug, Paxlovid, which was granted Emergency Use Authorization by the FDA for the treatment of COVID-19. PF-07817883 was granted Fast Track designation and recently completed a Ph. II clinical trial in outpatient adults with COVID-19 symptoms. This article details the discovery strategy for PF-07817883, which includes addressing metabolic soft spots identified through MetID studies, recent clinical developments, and more.

Whereas covalent drugs were once considered risky for indications other than cancer due to the potential for idiosyncratic drug-induced liver injury and other toxicities, concerns appear to have softened as an increasing number of non-oncology covalent inhibitor programs have achieved successful outcomes. Here we highlight several recent anecdotes in covalent inhibitor drug discovery that seem to reflect these changing attitudes, including billion-dollar acquisitions and approvals outside oncology, and a few modern examples that showcase the increasingly rich science in this area.

KIN-3248 (Kinnate Biopharma) is a next-generation, irreversible, pan-fibroblast growth factor receptor inhibitor (FGFRi) in a first-in-human (FIH) dose-escalation study (NCT05242822) in adults with advanced tumors harboring FGFR2 and FGFR3 gene alterations. The program is an excellent case study for rational covalent drug design to address kinase mutations while maintaining sufficient PK properties for oral daily dosing in humans.

STX-721 is an oral, covalent, mutant-selective inhibitor of EGFR and HER2 Exon 20 insertion (ex20ins) mutants, a well-validated target that saw its first approval with mobocertinib in 2022. Inhibition of wild-type (WT) EGFR is well-established to cause skin and gut toxicities, and selective inhibition of EGFR ex20ins mutants over WT may also allow greater efficacy to be seen at tolerated doses. This is an excellent case study for PK optimization with a covalent inhibitor, and [...]

In Wednesday’s Flash Talk webinar, we covered recent highlights in covalent drug discovery, with lots of great questions from the audience. The webinar and recording are available below to everyone thanks to our sponsor, Revvity Signals, and the slides are available for download to Premium members at the bottom.

Genentech’s divarasib is a KRASG12C inhibitor in Ph. III for non-small cell lung cancer, making it the most advanced KRASG12C inhibitor after the accelerated approvals of Amgen’s sotorasib and Mirati’s adagrasib. Efficacy with the molecule positions it well at a pivotal moment following sotorasib's recent FDA setback and BMS’s acquisition of adagrasib. Why divarasib is a big deal and what's notable about it in this full article.

Last year, Biogen announced that it would acquire Texas biotech Reata Pharmaceuticals for $7.3B. Reata’s lead molecule, omaveloxolone (SKYCLARYS®), an oral, reversible covalent inhibitor of the E3 ligase KEAP1, became the first drug approved for Friedrich’s Ataxia. Omaveloxolone was previously highlighted as a Molecule of the Month in July 2023. Now, this 2023 Molecule of the Year nominee reflects a historic milestone for neurological drug discovery. This comprehensive explainer dives into Nrf2 target rationale, how it works, how the drug was discovered, its synthesis, and why it’s a big deal.

The FGFR family of receptors are well-validated targets in cancer. While specific FGFRs like FGFR2 can drive cancers like cholangiocarcinoma, broad inhibition of FGFRs leads to significant off-target toxicities. Relay Therapeutics captured industry attention when they announced the discovery of an FGFR2 isoform-selective inhibitor, lirafugratinib, using a molecular dynamics simulations approach. This article provides an overview of the pan-FGFR landscape, explores the specifics of the FGFR2 selectivity, preclinical pharmacology, and early clinical data for this remarkable molecule.

Recently, Novartis disclosed a new class of brain-penetrant, covalent agents against kinetoplastid parasites in Science. Kinetoplastid parasites cause Chagas disease (T. cruzi), sleeping sickness (T. brucei), and leishmaniasis (Leishmania), but there are few effective treatment options, especially for infections in the brain (e.g. stage II sleeping sickness).

AZD4747 is a CNS-penetrant, oral KRAS G12C covalent inhibitor for the treatment of CNS-metastatic KRAS-mutant cancers. KRAS inhibitors have tended to be quite large and fall outside the range of physicochemical properties generally required for CNS permeability. (MW < 360 Da, cLogD < 2, TPSA < 90 Å2. AZD4747 is much smaller than marketed KRAS G12C inhibitors but maintains exceptional cellular potency. The team also encountered an unexpected toxicity that scientists working on covalents should pay attention to.

Pfizer’s ritlecitinib, a first-in-class, selective, oral covalent inhibitor of JAK3 and the TEC family of kinases, was FDA-approved in June 2023 for the treatment of severe alopecia areata. Ritlecitinib derives its JAK-family kinase selectivity from the covalent modification of a unique cysteine on JAK3. This annotation reviews the discovery of ritlecitinib, highlighting the interpretation of selectivity assays, the PK optimization, the evolution of the JAK3 therapeutic hypothesis, and how this 2023 Molecule of the Year nominee has become a classic case study for covalent drug discovery.

The accelerated approvals of Ras(OFF)-targeting KRAS G12C inhibitors sotorasib and adagrasib, decades in the making, marked the beginning of a new phase of KRAS drug discovery. While an increasing number of follow-on KRAS inhibitors are emerging with similar mechanisms of action, Revolution Medicines’ 2023 Molecule of the Year Nominee, RMC-6291, is representative of a completely novel approach that could become a strong addition to the clinical toolbox for KRAS, but also serves as proof-of-concept for a new class of small molecule therapeutics entirely.

FGF401 (roblitinib) is a highly selective, reversible-covalent inhibitor of the kinase FGFR4, a receptor that can drive progression of certain cancers. The Novartis team found that the FGFR4 protein has a high re-synthesis rate and therefore would require significant drug exposure to have a meaningful effect, so they deprioritized [...]

April 2020’s molecule, the Mirati KRAS G12C inhibitor MRTX849 , has been a hotly followed compound in development as it is the closest clinical KRAS inhibitor to the likely soon-to-be approved AMG-510 (sotorasib). The KRAS clinical race easily would have been the most followed development story of 2020 had it not been for COVID, due to the [...]

Voxelotor is a first-in-class, reversible covalent aldehyde drug that prevents the hemoglobin polymerization, a primary driver of sickle cell disease. Approved in 2019 , this molecule represented a scientific milestone as a modern example of a reversible covalent drug being approved in a chronic indication. It is the first oral drug that [...]

Futibatinib (Lytgobi) is a rare alkyne-containing, irreversible FGFR1-4 inhibitor that received accelerated approval from the FDA in September 2022. Structurally distinct from other approved FGFR2/3 inhibitors, futibatinib treats a range of FGFR-aberrant tumors, including those with fusions or TKI-resistant mutants like the V565I/L gatekeeper [...]

Context. AN15368 (Anacor Pharmaceuticals) is an oral Cleavage And Polyadenylation Specificity Factor (CPSF3) inhibitor being developed for Chagas disease, also known as American trypanosomiasis. Chagas disease is caused by Trypanosoma cruzi and is estimated to affect 6-7 million people worldwide, primarily those living in Latin America. The [...]

Context. JNJ-64264681 (Janssen) is a covalent Bruton’s tyrosine kinase (BTK) inhibitor being developed for hematological malignancies. The first-in-class irreversible BTKi ( ibrutinib ) was approved in 2013, while many others have been approved or are in clinical development with potentially reduced off-target effects . We recently covered [...]

Abstract. Voxelotor, a gram-daily reversible covalent aldehyde drug, is an approved first-in-class oral drug that prevents the hemoglobin polymerization that drives sickle cell disease. It was one of several agents in clinical trials acquired from Global Blood Therapeutics by Pfizer as part of an over $5 billion buyout. In this article, we [...]

“Compound 3” (UCSF) is a covalent KRAS G12R inhibitor used as a proof-of-concept for covalent arginine modification. KRAS is the first oncoprotein to be identified and is a well-known cancer-driving protein. As one of the most frequently mutated proteins in pancreatic and colorectal cancers, residues that are frequently mutated are [...]

Context. AZD4831 (AstraZeneca) is an oral covalent myeloperoxidase (MPO) inhibitor being developed for heart failure. Almost half of chronic heart disease patients suffer from heart failure with a preserved ejection fraction (HFpEF) and have an estimated five-year mortality rate of 75% . Improvement in vascular structure could help these [...]

Context. BI-4142 (Boehringer Ingelheim) is a HER2 exon 20 insertion mutant inhibitor being developed for non-small cell lung cancer (NSCLC). Despite the general advances made in HER2-targeted therapy and the existence of several agents targeting HER2-positive breast cancer , a high unmet need exists for patients with HER2 mutant NSCLC [...]

Context. CC-99677 (BMS) is an oral, covalent MAPK–activated protein kinase-2 (MK2) inhibitor being developed for autoimmune diseases. Although p38 is the most heralded member of the p38-MAPK signaling pathway, one that mediates the release of pro-inflammatory cytokines and is implicated in several inflammatory diseases, attempts to directly [...]

Context. JDQ443 (Novartis Institute for Biomedical Research) is an oral KRAS^G12C inhibitor being developed for various advanced solid tumors . Despite accounting for 85% of RAS oncogenic mutations in all cancers, KRAS was considered undruggable until 2013 when a report describing the targetability of the KRAS^G12C mutant by small molecule [...]

We asked the global drug discovery community to nominate and vote on their favorite molecule from 2021, and the results are in. The 2021 choice for Drug Hunter’s Small Molecule of the Year is Pfizer’s CoV-2 M pro Inhibitor, PF-07321332 (nirmatrelvir, Paxlovid) . Published in a November 2021 Science article , the molecule was praised for its [...]

Pfizer’s PF-07321332 (API of Paxlovid) is an oral, reversible covalent SARS-CoV-2 main protease inhibitor, which received emergency use authorization from the FDA for Covid treatment at the end of 2021. Clinical data showed Paxlovid reducing Covid hospitalization and death by 89%. It was nominated for November’s cover by Mike Koehler [...]

The ARIAD/Takeda EGFR exon 20 insertion mutant (EGFRex20ins) inhibitor TAK-788 is a Breakthrough Therapy for patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor EGFR exon 20 insertion mutations.  The appearance of exon 20 insertions is a common resistance mechanism to earlier generations of EGFR inhibitors including [...]

This month’s cover molecule, Pfizer’s PF-07321332 (nirmatrelvir, API of Paxlovid) is an oral, reversible covalent SARS-CoV-2 main protease inhibitor, which has been submitted to the FDA by Pfizer for emergency approval for Covid treatment. Interim data showed Paxlovid reducing Covid hospitalization and death by 89%. It was nominated for this month’s [...]

The Entasis broad-spectrum antibiotic, ETX0462 , is both an inhibitor of penicillin-binding proteins (PBPs, the target of beta-lactams) and a beta-lactamase inhibitor (BLI). Reviewer Mike Koehler thought this was a substantial disclosure. “A number of BLIs co-formulated with carbapenems and monobactams are currently on the market. There are a [...]

FGF401 (roblitinib) is a highly selective, reversible-covalent inhibitor of the kinase FGFR4, a receptor that can drive progression of certain cancers. The Novartis team found that the FGFR4 protein has a high re-synthesis rate and therefore would require significant drug exposure to have a meaningful effect, so they deprioritized [...]

April 2020’s molecule, the Mirati KRAS G12C inhibitor MRTX849 , has been a hotly followed compound in development as it is the closest clinical KRAS inhibitor to the likely soon-to-be approved AMG-510 (sotorasib). The KRAS clinical race easily would have been the most followed development story of 2020 had it not been for COVID, due to the [...]

QPX7728 is an ultrabroad-spectrum beta-lactamase inhibitor with activity against both serine and zinc metallo-beta-lactamases, in contrast to approved beta-lactamase inhibitors such as relebactam which are only active against serine metalloproteases. Interestingly, the boron of the molecule coordinates to serine hydroxyl groups in serine [...]

FT385 is a covalent inhibitor of the USP30 deubiquitinating enzyme with a cyanopyrrolidine warhead. Identifying selective active-site inhibitors of de-ubiquitinating enzymes has been challenging, and FT385 now provides a good tool compound to study USP30 biology. Some of my colleagues at Genentech recently published on the mechanism of [...]

Sulfopin (Weizmann/Harvard selective covalent Pin1 inhibitor)

Remibrutinib (Novartis oral BTK-selective covalent kinase inhibitor clinical candidate)

KRAS(G12C) inhibitor from AZ (AstraZeneca oral in vivo mutant KRAS(G12C) allosteric covalent inhibitor)

On Feb. 16, 12:00PM PST, Dr. Mira Pochon, Staff Scientist and Head of Translational Biology at Global Blood Therapeutics, gave a PBSS/CLSA webinar on one of 2019's drug approvals , voxelotor (GBT440).  Mira has been with GBT since it’s early days in 2011.  GBT’s chemistry team was led by their CSO Dr. Brian Metcalf, former head of drug [...]