KIN-3248: Overcoming FGFR Resistance with a Next-Generation Pan-FGFR Inhibitor

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.

KIN-3248 (Kinnate Biopharma) is a next-generation, irreversible, pan-fibroblast growth factor receptor inhibitor (FGFRi) in a firs...

STX-721

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 [...]

STX-721 is an oral, covalent, mutant-selective inhibitor of EGFR and HER2 Exon 20 insertion (ex20ins) mutants, a well-validated ta...

Recent Highlights in Covalent Drug Discovery

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.

In Wednesday’s Flash Talk webinar, we covered recent highlights in covalent drug discovery, with lots of great questions from the ...

divarasib

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.

Genentech’s divarasib is a KRASG12C inhibitor in Ph. III for non-small cell lung cancer, making it the most advanced KRASG12C inhi...

omaveloxolone

This year, Biogen announced that it would acquire Texas biotech Reata Pharmaceuticals for $7.3B. Omaveloxolone is the first drug approved for Friedrich’s Ataxia. This comprehensive explainer dives into Nrf2 and its history and target rationale, how omaveloxolone works, how the drug was discovered and made its way from an academic cancer drug to approval for Friedreich’s ataxia, whether liver enzyme elevations should be concerning, its synthesis, and more.

This year, Biogen announced that it would acquire Texas biotech Reata Pharmaceuticals for $7.3B. Omaveloxolone is the first drug a...

lirafugratinib (RLY-4008)

The FGFR family of receptors are well-validated targets in cancer, and several pan-FGFR inhibitors that have strong activity against FGFR1-4 have reached approval including pemigatinib, infigratinib, futibatinib, and erdafitinib. While specific FGFRs like FGFR2 can drive cancers like cholangiocarcinoma, broad inhibition of FGFRs leads to significant off-target toxicities, such as hyperphosphatemia from FGFR1 inhibition or diarrhea from FGFR4 inhibition.

The FGFR family of receptors are well-validated targets in cancer, and several pan-FGFR inhibitors that have strong activity again...

CT3

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).

Recently, Novartis disclosed a new class of brain-penetrant, covalent agents against kinetoplastid parasites in Science. Kinetopla...

AZD4747

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.

AZD4747 is a CNS-penetrant, oral KRAS G12C covalent inhibitor for the treatment of CNS-metastatic KRAS-mutant cancers. KRAS inhibi...

ritlecitinib

Pfizer’s ritlecitinib (PF-06651600), a first-in-class, selective, oral covalent inhibitor of Janus kinase 3 (JAK3) and the TEC family of kinases, was recently FDA approved in June 2023 for the treatment of an autoimmune hair loss condition (severe alopecia areata). The molecule is derived from tofacitinib, an approved JAK1/3 inhibitor that Pfizer originally believed was a selective JAK3 inhibitor based on biochemical data, but turned out to be equally active against JAK1 in cellular contexts.

Pfizer’s ritlecitinib (PF-06651600), a first-in-class, selective, oral covalent inhibitor of Janus kinase 3 (JAK3) and the TEC fam...

RMC-6291

And now for something completely different. The recent approvals of Ras(off)-targeting KRAS G12C inhibitors sotorasib and adagrasib, decades in the making, mark the beginning of a new phase of KRAS drug discovery. Clinical data with both molecules suggest that there are opportunities for brain-penetrant KRAS inhibitors, [...]

And now for something completely different. The recent approvals of Ras(off)-targeting KRAS G12C inhibitors sotorasib and adagrasi...

FGF401 (roblitinib)

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 [...]

FGF401 (roblitinib) is a highly selective, reversible-covalent inhibitor of the kinase FGFR4, a receptor that can drive progressio...

MRTX849

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 [...]

April 2020’s molecule, the Mirati KRAS G12C inhibitor MRTX849 , has been a hotly followed compound in development as it is the clo...

GBT/Pfizer HbS polymerization inhibitor

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 [...]

Voxelotor is a first-in-class, reversible covalent aldehyde drug that prevents the hemoglobin polymerization, a primary driver of ...

The First Approved Covalent pan-FGFR1-4 Kinase Inhibitor, Futibatinib

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 [...]

Futibatinib (Lytgobi) is a rare alkyne-containing, irreversible FGFR1-4 inhibitor that received accelerated approval from the FDA ...

AN15368

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. AN15368 (Anacor Pharmaceuticals) is an oral Cleavage And Polyadenylation Specificity Factor (CPSF3) inhibitor being devel...

JNJ-64264681

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 [...]

Context. JNJ-64264681 (Janssen) is a covalent Bruton’s tyrosine kinase (BTK) inhibitor being developed for hematological malignanc...

Billion-Dollar Molecules: Voxelotor, A $5.4 Billion Reversible Covalent Aldehyde

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 [...]

Abstract. Voxelotor, a gram-daily reversible covalent aldehyde drug, is an approved first-in-class oral drug that prevents the hem...

compound 3

“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 [...]

“Compound 3” (UCSF) is a covalent KRAS G12R inhibitor used as a proof-of-concept for covalent arginine modification. KRAS is the f...

AZD4831

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. AZD4831 (AstraZeneca) is an oral covalent myeloperoxidase (MPO) inhibitor being developed for heart failure. Almost half ...

BI-4142

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. BI-4142 (Boehringer Ingelheim) is a HER2 exon 20 insertion mutant inhibitor being developed for non-small cell lung cance...

CC-99677

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. CC-99677 (BMS) is an oral, covalent MAPK–activated protein kinase-2 (MK2) inhibitor being developed for autoimmune diseas...

JDQ443

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 [...]

Context. JDQ443 (Novartis Institute for Biomedical Research) is an oral KRAS^G12C^ inhibitor being developed for various advanced ...

Nirmatrelvir: 2021 Small Molecule of the Year

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 [...]

We asked the global drug discovery community to nominate and vote on their favorite molecule from 2021, and the results are in. Th...

Pfizer CoV-2 MPro Inhibitor

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 [...]

Pfizer’s PF-07321332 (API of Paxlovid) is an oral, reversible covalent SARS-CoV-2 main protease inhibitor, which received emergenc...

Takeda EGFRex20 Inhibitor

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 [...]

The ARIAD/Takeda EGFR exon 20 insertion mutant (EGFRex20ins) inhibitor TAK-788 is a Breakthrough Therapy for patients with advance...

paxlovid

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 [...]

This month’s cover molecule, Pfizer’s PF-07321332 (nirmatrelvir, API of Paxlovid) is an oral, reversible covalent SARS-CoV-2 main ...

ETX0462

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 [...]

The Entasis broad-spectrum antibiotic, ETX0462 , is both an inhibitor of penicillin-binding proteins (PBPs, the target of beta-lac...

FGF401 (roblitinib)

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 [...]

FGF401 (roblitinib) is a highly selective, reversible-covalent inhibitor of the kinase FGFR4, a receptor that can drive progressio...

MRTX849

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 [...]

April 2020’s molecule, the Mirati KRAS G12C inhibitor MRTX849 , has been a hotly followed compound in development as it is the clo...

QPX7728

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 [...]

QPX7728 is an ultrabroad-spectrum beta-lactamase inhibitor with activity against both serine and zinc metallo-beta-lactamases, in ...

FT385

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 [...]

FT385 is a covalent inhibitor of the USP30 deubiquitinating enzyme with a cyanopyrrolidine warhead. Identifying selective active-s...

sulfopin

Sulfopin (Weizmann/Harvard selective covalent Pin1 inhibitor)

Sulfopin (Weizmann/Harvard selective covalent Pin1 inhibitor) ...

remibrutinib

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

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

"compound 25"

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

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

A Gram-Daily Aldehyde for Anemia: Voxelotor

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 [...]

On Feb. 16, 12:00PM PST, Dr. Mira Pochon, Staff Scientist and Head of Translational Biology at Global Blood Therapeutics, gave a P...