2. Academic Validation
  3. A three-step protocol for lead optimization: quick identification of key conformational features and functional groups in the SAR studies of non-ATP competitive MK2 (MAPKAPK2) inhibitors

A three-step protocol for lead optimization: quick identification of key conformational features and functional groups in the SAR studies of non-ATP competitive MK2 (MAPKAPK2) inhibitors

  • Bioorg Med Chem Lett. 2012 Jan 1;22(1):65-70. doi: 10.1016/j.bmcl.2011.11.074.
Xianhai Huang 1,  Xiaohong Zhu,  Xiao Chen,  Wei Zhou,  Dong Xiao,  Sylvia Degrado,  Robert Aslanian,  James Fossetta,  Daniel Lundell,  Fang Tian,  Prashant Trivedi,  Anandan Palani
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. xianhai.huang@merck.com
PMID: 22169260 DOI: 10.1016/j.bmcl.2011.11.074
Abstract

A three-step protocol for SAR development was introduced and applied to the SAR studies of the MK2 inhibitor program. Following this protocol, key conformational features and functional groups for improving MK2 inhibitor activity were quickly identified. Through this effort, the initial gap observed between in vitro binding activity and cellular activity in the lead identification stage was very much reduced. Compound 28 was identified with single digit binding activity (IC(50)=8 nM) and good cellular activity (EC(50)=310 nM). This provides further evidence that non-ATP-competitive binding MK2 inhibitors are feasible by targeting the outside ATP pocket.

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