Article
    February 2024 was filled with notable scientific achievements and partnerships. Gilead and Novartis inked billion-dollar acquisitions, and Novo Nordisk and NeoMorph agreed to a $1.46B deal to discover molecular glue degraders. Additionally, Vertex introduced a promising new treatment for cystic fibrosis that is potentially superior to Trikafta. Takeda also made strides by advancing their OX2R agonist TAK-861, for treating narcolepsy type 1, into Ph. III clinical trials. Read this news roundup for more details on these and other drug discovery news stories that you may have missed from Feb 2024
    Article
    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.
    Molecule
    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.
    Molecule
    Gamma-secretase is most well-known as a target for Alzheimer’s disease, though such programs have not been successful to date. Nirogacestat is a gamma-secretase inhibitor that Pfizer originally intended to treat AD, but found life at Springworks Therapeutics as a treatment as a first-in-class drug for rare and aggressive desmoid tumors (DTs). Nirogacestat received the first FDA approval for a treatment for desmoid tumors in Nov. 2023, and this article reviews how it was discovered, how the therapeutic hypothesis emerged after confusing assay disconnects, and lessons learned from the program.
    Molecule
    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.