title: 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.
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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. xianhai.huang@merck.com
authors.forename: Xianhai
authors.initials: X
authors.lastname: Huang
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhu
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Dong
authors.initials: D
authors.lastname: Xiao
authors.forename: Sylvia
authors.initials: S
authors.lastname: Degrado
authors.forename: Robert
authors.initials: R
authors.lastname: Aslanian
authors.forename: James
authors.initials: J
authors.lastname: Fossetta
authors.forename: Daniel
authors.initials: D
authors.lastname: Lundell
authors.forename: Fang
authors.initials: F
authors.lastname: Tian
authors.forename: Prashant
authors.initials: P
authors.lastname: Trivedi
authors.forename: Anandan
authors.initials: A
authors.lastname: Palani
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008956:Models, Chemical; D008968:Molecular Conformation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000255:Adenosine Triphosphate; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2