Abstract
Protein tyrosine phosphatase SHP2 is an oncoprotein associated with cancer as well as a potential immune modulator due to its role in the programmed cell death PD-L1/PD-1 pathway. Small ...molecule inhibition of SHP2 has been widely investigated including our previous reports describing SHP099, which binds to a tunnel-like allosteric binding site. To broaden our approach to allosteric inhibition of SHP2, we conducted additional hit finding, evaluation, and structure-based scaffold morphing. These studies led to the identification of multiple, potent inhibitor chemotypes, an additional and distinct allosteric binding site, and the identification of SHP394, an orally efficacious inhibitor of SHP2 with improved potency and enhanced pharmacokinetic properties. Overall, this work improves upon our previously described allosteric inhibitors, and exemplifies and extends the range of permissible chemical templates that inhibit SHP2 via the allosteric mechanism.
Citation Format: Matthew J. LaMarche, Jeff Bagdanoff, Mike Acker, Ying-Nan Chen, Homan Chan, Michael Dore, Brant Firestone, Michelle Fodor, Jorge Garcia-Fortanet, Murphy Hentemann, Mitsunori Kato, Robert Koenig, Laura La Bonte, Shumei Liu, Movarid Mohseni, Rukundo Ntaganda, Patrick Sarver, Troy Smith, Martin Sendzik, Travis Stams, Stan Spence, Chris Towler, Hongyun Wang, Ping Wang, Sarah Williams, Zhouliang Chen, Huaixiang Hao, Gang Liu, Chen Liu, Eric McNeill, Bing Yu. Allosteric SHP2 phosphatase inhibition: Multiple mechanisms and chemotypes abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-005.
Sphingosine 1-phosphate lyase (S1PL) has been characterized as a novel target for the treatment of autoimmune disorders using genetic and pharmacological methods. Medicinal chemistry efforts ...targeting S1PL by direct in vivo evaluation of synthetic analogues of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI, 1) led to the discovery of 2 (LX2931) and 4 (LX2932). The immunological phenotypes observed in S1PL deficient mice were recapitulated by oral administration of 2 or 4. Oral dosing of 2 or 4 yielded a dose-dependent decrease in circulating lymphocyte numbers in multiple species and showed a therapeutic effect in rodent models of rheumatoid arthritis (RA). Phase I clinical trials indicated that 2, the first clinically studied inhibitor of S1PL, produced a dose-dependent and reversible reduction of circulating lymphocytes and was well tolerated at dose levels of up to 180 mg daily. Phase II evaluation of 2 in patients with active rheumatoid arthritis is currently underway.
During nearly a decade of research dedicated to the study of sphingosine signaling pathways, we identified sphingosine-1-phosphate lyase (S1PL) as a drug target for the treatment of autoimmune ...disorders. S1PL catalyzes the irreversible decomposition of sphingosine-1-phosphate (S1P) by a retro-aldol fragmentation that yields hexadecanaldehyde and phosphoethanolamine. Genetic models demonstrated that mice expressing reduced S1PL activity had decreased numbers of circulating lymphocytes due to altered lymphocyte trafficking, which prevented disease development in multiple models of autoimmune disease. Mechanistic studies of lymphoid tissue following oral administration of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI) 3 showed a clear relationship between reduced lyase activity, elevated S1P levels, and lower levels of circulating lymphocytes. Our internal medicinal chemistry efforts discovered potent analogues of 3 bearing heterocycles as chemical equivalents of the pendant carbonyl present in the parent structure. Reduction of S1PL activity by oral administration of these analogues recapitulated the phenotype of mice with genetically reduced S1PL expression.
