Callie Bryan

Leniolisib is a selective PI3Kδ inhibitor that received approval in March 2023 from the FDA as a first-in-class treatment for activated PI3K-δ syndrome (APDS), a genetic immunodeficiency disorder caused by PI3Kδ activation. The leniolisib discovery program is notable for several reasons: it is a first approval for a PI3K inhibitor outside of oncology; the first approved drug for APDS; has a novel chemotype that appears to avoid safety issues that led to black box warnings seen with other PI3K molecules; and it overcame a polymorph issue with an early lead that led to inconsistent exposures.

This edition of Drug Hunter Letters highlights recent insightful communications from Drug Hunter readers, including: Simon Bury on the History of GSK’s Recently Acquired $1.9B JAK Inhibitor Callie Bryan and Bryan McKibben on Insulin Receptor Partial Agonists and Recent Oncology Highlights Jesse Keicher on CXCR1/2 Antagonists in Treating [...]

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. AZD4625 (AstraZeneca) is an oral inhibitor of KRAS G12C being developed for the treatment of advanced solid malignancies . As indicated for JDQ443, the KRAS G12C mutation presents the perfect “Achilles heel” for targeting a KRAS protein previously thought undruggable. The protein is a current hot topic in precision oncology , with [...]

JBJ-09-063 (Dana-Farber Cancer Institute) is an oral allosteric EGFR inhibitor currently in pre-clinical development for the treatment of EGFR L858R -mutant non-small cell lung cancer (NSCLC) . Despite the availability of 3 generations of EGFR TKIs for the treatment of EGFR-mutant NSCLC, drug resistance and associated disease [...]

“Compound 10” (AstraZeneca) is an oral CDK5-mediated PPARγ phosphorylation inhibitor and partial PPARγ agonist being developed as an antidiabetic drug . Although widely used PPARγ agonists such as rosiglitazone and pioglitazone are effective antidiabetics, they are limited by [...]

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 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 Janssen non-ATP competitive HPK1 inhibitor, “ compound 1 ,” was identified from a screening cascade specifically looking for allosteric inhibitors, which may provide a selectivity advantage over ATP-competitive starting points. Reviewer Adi Murthy says, “ Specificity may prove challenging for HPK active site inhibitors since it belongs to [...]