Astinova Blog
Working notes from the Astinova chemistry team — synthesis case studies, modality deep dives, and observations from real drug discovery programs.
Mechanism: Lirafugratinib (RLY-4008) is a highly selective, IRREVERSIBLE (covalent) small-molecule inhibitor of fibroblast growth factor receptor 2 (FGFR2). A methacrylamide (2-methylprop-2-enamide) Michael-acceptor warhead covalently engages Cys491 at the tip of the FGFR2 phosphate-binding (P)-loop (homologous Cys488 in FGFR1). Selectivity…
Read article →Mechanism: A degrader-antibody conjugate is an ADC whose payload is not a cytotoxin but a heterobifunctional protein degrader — a PROTAC or a molecular glue. The antibody supplies antigen-restricted delivery and IgG-like pharmacokinetics; the payload supplies a catalytic, sub-stoichiometric…
Read article →Mechanism: Iberdomide is a potent, orally available cereblon (CRBN) E3 ligase modulator (CELMoD). It binds CRBN — the substrate receptor of the CRL4^CRBN E3 ubiquitin ligase — and reshapes the substrate-recruitment surface to drive ubiquitination and proteasomal degradation of…
Read article →Mechanism: Brepocitinib is an oral, Type I (ATP-competitive) inhibitor that reversibly binds the catalytic JH1 kinase domain of BOTH tyrosine kinase 2 (TYK2; ChEMBL CHEMBL3553) and Janus kinase 1 (JAK1; CHEMBL2835), with relative JAK2/JAK3 sparing (enzymatic IC50 ~TYK2 23…
Read article →Mechanism: Daraxonrasib (RMC-6236) is an oral, noncovalent, beyond-Rule-of-5 macrocyclic ‘tri-complex’ (molecular-glue) inhibitor of RAS. It first binds the intracellular chaperone cyclophilin A (CypA); the drug–CypA binary complex then presents a neomorphic composite surface that engages the active, GTP-bound (‘ON’)…
Read article →Why this molecule is special Deucravacitinib (BMS-986165, brand name Sotyktu) is a first-in-class, oral TYK2 inhibitor approved for plaque psoriasis and being pursued across a range of autoimmune diseases — psoriatic arthritis, lupus, inflammatory bowel disease. It is unusual on two…
Read article →Why cyclic peptides matter Drug discovery has long been split between two worlds: small molecules (cheap, oral, cell-permeable, but often unable to grip large flat protein surfaces) and biologics (exquisitely specific, but injectable, expensive, and locked out of the cell). Cyclic peptides…
Read article →Compiled: 2026-08-14 · Trigger event: FDA approval, 2025-03-25 Innovator: GlaxoSmithKline LLC (US NDA holder; composition-of-matter patents held by Glaxo Group Limited). Developed with US government biodefense co-funding (BARDA OTA HHSO100201300011C; DoD/DTRA HDTRA1-07-9-0002). Status: Approved NME Mechanism: Gepotidacin is a first-in-class, bactericidal TRIAZAACENAPHTHYLENE antibacterial that inhibits bacterial…
Read article →The switch that runs your day Deep in the hypothalamus, a small population of neurons produces two neuropeptides — orexin-A and orexin-B (also called hypocretin-1 and -2). They are the master “stay awake” signal, acting on two G-protein-coupled receptors, OX1R and OX2R. Of…
Read article →Why fluorinated amino acids, and why the (R)-series? Non-canonical amino acids are the building blocks of modern peptide drugs and designer biomaterials, and fluorine is one of the most powerful edits a chemist can make to one. Swapping a C–H…
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