Re-engineered MCC950 analog gives longer-lasting, orally exposed NLRP3 inhibition with cleaner tolerability
- Tuning the lipophilic and solvent-facing portions of the sulfonylurea MCC950 gave F34, which keeps nanomolar cellular potency and spares the NLRC4 and AIM2 inflammasomes.
- Docking and molecular dynamics place F34 in the MCC950 site; SPR shows direct, micromolar binding to NLRP3.
- In mice F34 has a long half-life and very high oral bioavailability, and outperforms MCC950 in gout and chronic colitis models, with better tolerability and low hERG and CYP liabilities.
💡 Points Based on the abstract
Compared with MCC950 and the newer sulfonylurea-free NLRP3 chemotypes, F34 is a conservative edit: the acidic sulfonylurea core, and its liver-safety question, is still there. Docking plus SPR is thin for a binding-mode claim, so I'd want a cryo-EM or co-crystal structure with NLRP3, and chronic-dosing liver data, before believing the improved tolerability.