Where Do Recent Small Molecule Clinical Candidates Come From?
Modern hit-finding technologies are incredible. Dean Brown and Jonas Bostrom at AstraZeneca have a very nice review out summarizing the hit-finding strategies for 66 clinical candidates published from 2016-2017. Some highlights include a clinical candidate from DNA-encoded libraries at GSK, the discovery of an RNA-binding drug candidate by PTC/Roche, and fragment-based programs with candidates 100,000x…
Adventures in Atropisomerism: A Case Study from BMS
BMS-986142 is a reversible BTK inhibitor with two axial stereocenters. BMS synthetic chemists were able to make >200 kilos of this compound as a single isomer using this route. Wow. Atropisomers are a nightmare in drug discovery. Axial stereocenters are not easy to set predictably, separation of isomers is a pain, and the products are…
That Jimmy Carter Drug
Checkpoint inhibitors like pembrolizumab (Keytruda) have revolutionized treatment for many late-stage cancer patients, including Jimmy Carter. Recently, Keytruda stunned the world again with efficacy in metastatic non-small cell lung cancer, the leading cancer killer. Here’s a summary of its recent successes and the surprising path Keytruda took through two acquisitions and the Merck “out-license” list.…
A Trick to Fluorinate Grignards
Knochel’s group has shown that you can fluorinate Grignard reagents without decomposition via single-electron transfer reactivity (SET) by a simple solvent switch from THF to DCM. A common way to prepare aryl fluorides is through lithium-halogen exchange, followed by trapping with N-fluorosulfonimide (NFSI). This isn’t always viable, as the alkyllithium reagents used in the exchange…
The Post-Gleevec Era
Gleevec (imatinib) was the first tyrosine kinase inhibitor approved for the treatment of cancer and one of the first products to emerge from “rational drug design.” It’s invention changed chronic myeloid leukemia from an incurable death sentence to a manageable disease. Here’s a look back on the tremendous value it’s created over the last two…