1H-Indole-4-carboxamide, 2-methyl-1-[5,6,7,8-tetrahydro-4-[(phenylmethyl)amino]pyrido[2,3-d]pyrimidin-2-yl]-

CB-5339 is a second generation, potent and selective, orally bioavailable, ATP-competitive, small molecule inhibitor of valosin containing protein (VCP)/p97 [1,2]. CB-5339 is an ATP-competitive, small molecule inhibitor of p97 with IC50 of 53 nM [3]. CB-5339 effectively effect on a panel of 16 primary AML patient samples harboring diverse genetic backgrounds. The median IC50 value was 375 nM among these samples [1]. CB-5339 (200 to 1000 nM for 48 hours) induces in vitro loss of viability in AML cell lines (OCI-AML3, MOLM13, SET2 and HEL92.1.7 cells), as well as in fresh, patient-derived (PD) AML cells, including those with TP53 mutations and/or TP53 allelic loss, or with 3q26 (MECOM locus) lesions and EVI1 overexpression [2]. CB-5339 induced accumulation of polyubiquitylated proteins, retention of ERAD substrates, and lethal ER stress in cancer cells mediated by CHOP, DR5 and NOXA [2]. CB-5339 has higher bioavailability than CB-5083 [1]. Treatment with CB-5339 (90 mg/kg) reduced invasion of myeloid leukemia and prolonged survival in an MLL-AF9-driven PDX AML mouse model [1]. In a tail-vein infused, luciferase transduced, aggressive xenograft model of MOLM13 cells, after AML engraftment, co-treatment for 3 weeks with CB-5339 (50 mg/kg/day, PO) and either venetoclax (30 mg/kg/day, PO) or OTX015 (30 mg/kg/day, PO), as compared to treatment with vehicle or each drug alone, significantly reduced the AML burden and improved median and overall survival of the NSG mice, without inducing significant toxicity [2].

[1]. B Roux B, Vaganay C, Vargas J D, et al. Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation small-molecule inhibitor[J]. Science translational medicine, 2021, 13(587): eabg1168.[2]. Fiskus W C, Das K, Mill C P, et al. Efficacy of Vcp/p97 Inhibitor, CB-5339, Alone and in Combinations Against High-Risk AML, Including Those with Genetic Lesion in TP53[J]. Blood, 2022, 140(Supplement 1): 8807-8808.[3]. Wang X, Wen T, Miao H, et al. Discovery of a new class of valosine containing protein (VCP/P97) inhibitors for the treatment of colorectal cancer[J]. Bioorganic & Medicinal Chemistry, 2022, 74: 117050.