• John Malona, Claudio Chuaqui, Boris M Seletsky, Lisa Beebe, Susan Cantin, Daniel VAN Kalken, Kelly Fahnoe, Zhigang Wang, Beth Browning, Hilary Szabo, Louise A Koopman, Tamas Oravecz, Joseph J McDonald, Francisco Ramirez-Valle, Rajula Gaur, Kofi A Mensah, Michael Thomas, Jamie N Connarn, Haiqing Hu, Matthew D Alexander, and Alan F Corin.
• Bristol Myers Squibb, Princeton, New Jersey.
• Transl Res. 2022 Nov 1; 249: 497349-73.

AbstractAs an anti-inflammatory strategy, MAPK-activated protein kinase-2 (MK2) inhibition can potentially avoid the clinical failures seen for direct p38 inhibitors, especially tachyphylaxis. CC-99677, a selective targeted covalent MK2 inhibitor, employs a rare chloropyrimidine that bonds to the sulfur of cysteine 140 in the ATP binding site via a nucleophilic aromatic substitutions (SNAr) mechanism. This irreversible mechanism translates biochemical potency to cells shown by potent inhibition of heat shock protein 27 (HSP27) phosphorylation in LPS-activated monocytic THP-1 cells. The cytokine inhibitory profile of CC-99677 differentiates it from known p38 inhibitors, potentially suppressing a p38 pathway inflammatory response while avoiding tachyphylaxis. Dosed orally, CC-99677 is efficacious in a rat model of ankylosing spondylitis. Single doses, 3 to 400 mg, in healthy human volunteers show linear pharmacokinetics and apparent sustained tumor necrosis factor-α inhibition, with a favorable safety profile. These results support further development of CC-99677 for autoimmune diseases like ankylosing spondylitis.Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

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