Entrance-channel design tames cytotoxicity of the JK-4b NNRTI lead
- JK-4b, a potent NNRTI active against wild-type and clinical HIV-1 variants, was shelved because of high cytotoxicity; the authors used it as a lead for new analogues.
- Structure-guided designs addressing the NNRTI entrance channel gave a series with lower cytotoxicity and improved selectivity.
- Lead compound 9n retained strong potency against common resistance mutants, including double mutants, at levels comparable to etravirine.
- 9n also showed minimal cytochrome P450 inhibition and good human liver microsome stability, supporting further development.
💡 Points
Rescuing a shelved lead is always more interesting than starting cold: JK-4b already had the potency and resistance coverage, so the real question was whether entrance-channel contacts could decouple that from its cytotoxicity. If 9n's profile holds up, that suggests the toxicity was scaffold-tunable, not baked into the pharmacophore. Matching etravirine on double mutants while staying clean on P450 and microsome stability is what I'd want to see before making more.