TP-0903

TP-0903 is an inhibitor of the receptor tyrosine kinase Axl (IC₅₀ = 27 nM ).¹ It exhibits greater than 50% inhibition of 11 kinases, including MER, TYRO3, JAK2, ALK, and Abl1, in a panel of 75 kinases at 200 nM, with IC₅₀ values of 3 and 12.4 nM for Aurora A and B, respectively. TP-0903 decreases the phosphorylation of Akt and Axl in GAS6-stimulated, serum-starved PSN-1 pancreatic cancer cells (EC₅₀s = 305 and 222 nM, respectively). It decreases cell viability (IC₅₀ = 6 nM) and induces cell cycle arrest at the G₂/M phase in PSN-1 cells when used at a concentration of 30 nM. TP-0903 also reduces the viability of colorectal cancer (CRC) cell lines with IC₅₀ values ranging from 4.5 to 123 nM.² It exhibits 69 and 44% tumor growth inhibition in an HCT116 mouse xenograft model and a K-Ras-mutant CRC patient-derived xenograft (PDX) mouse model, respectively, when administered at a dose of 40 mg/kg.

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1. Mollard, A., Warner, S.L., Call, L.T., et al. Design, synthesis and biological evalutation of a series of novel Axl kinase inhibitors. ACS Med. Chem. Lett. 2(12), 907-912 (2011).

2. Mangelson, R., Peterson, P., Foulks, J.M., et al. Abstract 2197: The AXL kinase inhibitor, TP-0903, demonstrates efficacy in preclinical models of colorectal cancer independent of KRAS mutation status. Cancer Res. 79(13 Suppl), (2019).