Vanin-1 is a biotinidase (nitrilase superfamily) that hydrolyzes pantetheine. Despite the critical role of pantetheine, vanin-1 deficient mice don’t appear to have issues, but may be protected in inflammatory disease settings like IBD. Since human vanin-1 coverage requirements are unknown, the Pfizer vanin-1 program took a “no-regrets” [...]

LRRK2 is a target of interest for Parkinson’s disease (e.g. DNL-151 ), but development had been slowed by concerns about potential lung toxicity of LRRK2 inhibitors. A Phase I study of a LRRK2 inhibitor in healthy volunteers had not shown human toxicity, though, and Biogen/Denali plan to proceed with Ph. III and Ph. IIb trials in 2022 . The [...]

“Compound 25,” inhibits HPK1 via a rare “P-loop folded” active site conformation. The molecule was nominated by reviewer Julien Lefranc , and structural biologist Yoana Dimitrova shares some insight here: “The ‘folded P-loop’ conformation is considered “extremely unusual” – authors of a 2011 paper looked into this and found it in only 62 out [...]

New drugs are discovered by teams, not individuals. "Drug discovery is a complex undertaking, and I enjoy the collaboration with many people from different disciplines and expertise areas that it takes to solve this impossible puzzle," says reviewer Joachim Rudolph . Drug Hunter also takes a community to build, and we [...]

In 2022, Drug Hunter highlighted 120 Molecules of the Month with structures or stories that were published for the first time, were approved or disclosed new significant data. They were selected from tens of thousands of research articles published by leading institutions from around the world. Here is the final list of the top 10 candidates for 2022’s Molecule of the Year, nominated by our readers and reviewers. It's always incredibly hard to narrow down the group, and even harder to pick just one! These finalists are selected based on a variety of factors. There are four first-in-class compo...

The January 2022 edition of Drug Hunter’s Small Molecules of the Month includes a reversible CoV-2 main protease inhibitor from Shionogi in Ph. II/III which doesn’t require a PK booster like ritonavir, a recently disclosed oral, once-daily Factor XIa inhibitor, and the first-in-class STING agonist that was once Aduro’s lead. Thanks to reviewers for their feedback this month. Premium Members can save time gathering the key details behind each molecule with dedicated summaries and the Member’s slide deck. Alternatively, sign up for the free e-mail newsletter to get free previews of member conten...

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 Gilead SARS-CoV-2 drug, GS-621763, is an oral prodrug of the parent nucleoside of remdesivir (GS-441524) which demonstrated therapeutic and prophylactic efficacy in a ferret model of SARS-CoV-2 infection, significantly reducing viral load to near-undetectable levels with twice-daily administration. Remdesivir is already FDA [...]

The Astellas KRAS^G12C covalent inhibitor, ASP2453, is an oral molecule with activity in preclinical mouse models of KRASG12C-mutated cancer at lower doses than sotorasib (AMG 510). Several KRAS inhibitors have been highlighted recently. ASP2453 possesses an interesting spirocyclic azetidine-containing acrylamide warhead, and the [...]

The Syros Pharmaceuticals CDK7 kinase inhibitor, SY-5609, is a picomolar, reversible, and highly selective molecule with slow off-rate kinetics.  It follows a prior covalent clinical candidate from Syros. The molecule is >4000x selective vs. the nearest known off-target among 485 kinases profiled. Cyclin-dependent kinase inhibitors have [...]

The Biogen reversible BTK kinase inhibitor, BIIB091, is a highly selective, phase I clinical candidate for multiple sclerosis. Irreversible BTK inhibitors have been explored and developed extensively, primarily in cancer. Reversible molecules have been less common, with the most clinically advanced molecule being fenebrutinib (phase [...]

The Roche BRAF inhibitor, compound Ia, is designed to address the limitations of existing BRAFi/MEKi inhibitor combinations. It is a RAF paradox breaker (see belvarafenib) and is brain penetrant, offering the potential to address several mechanisms of resistance to approved agents and potentially reducing the need for MEKi combination [...]

The Daiichi Sankyo CDK8 kinase inhibitor, DS96432529, is intended to be a bone anabolic agent. The molecule shows preclinical efficacy and synergy with alendronate or parathyroid hormone. The discovery program was initiated well before the likely target (CDK8) was identified and provides an interesting retrospective case study for [...]

The Vertex ELOVL1 inhibitor, compound 27, is a potent (13 nM) CNS-penetrant compound that reduces very long chain fatty acid (VLCFA) levels in the CNS, which are believed to be pathological in the rare disease adrenoleukodystrophy (ALD). The starting point came from an HTS on compounds from an internal collection. The molecule demonstrated [...]

The Merck KGaA MET kinase inhibitor, tepotinib, was approved earlier this year for METex14 positive NSCLC patients, and is administered once-daily in contrast to capmatinib, which was approved in 2020. Both molecules were approved based on small numbers of patients (tepotinib pivotal trial: NCT02864992) due to the significance of the [...]

The Pfizer SAM-competitive PRMT5 inhibitor, PF-06939999 is a Ph. I clinical candidate in dose escalation in solid tumors. Ph. I data has been reported showing signs of early efficacy with cytopenias as common adverse events. This is in agreement with Ph. I data that was recently reported for a JNJ SAM-competitive PRMT5 inhibitor in [...]

The Genentech VPS34 kinase inhibitor, compound 5, is a selective kinase inhibitor that is unusually polar for a kinase inhibitor (logD = 1.0, PPB = 23%) but maintains low clearance. The article was nominated by reviewers Joachim Rudolph, Callie Bryan, Christian Kuttruff, and Julien Lefranc for its interesting tricyclic structure and [...]

The Dompé Farmaceutici TRPM8 blocker, compound 59 is a potent (IC50 = 11 nM) compound for painful ocular conditions, with ocular efficacy in a preclinical behavioral model. TRPM8 is a cation channel which is the predominant in mammalian cold thermosensor and it is activated by well-known molecules like menthol, eucalyptol, and geraniol [...]