Kit inhibitor APcK110 extends survival in an AML xenograft mouse model

Abstract

Summary Background Constitutive activation of kit contributes to pathogenesis of acute myeloid leukemia (AML) and targeting Kit may be of therapeutic benefit. APcK110, a novel inhibitor of Kit, has potent proapoptotic and antiproliferative activity in AML cell lines and primary AML samples. Here we extend our studies to the activity of APcK110 in a xenograft mouse model. Methods After sub-lethal whole body radiation, OCI/AML3 cells were injected intravenously in NOD-SCID mice. Ten days later, either APcK110 or phosphate buffered saline (PBS) was injected intraperitoneally every other day. Kaplan-Meier estimates were used to calculate survival. Results We show that 1) all mice injected with OCI/AML3 cells developed a clinical and histological picture consistent with myelomonocytic AML; and 2) survival of APcK110-treated mice was significantly longer compared with mice injected with PBS (p=.02). Conclusions APcK110 is a novel kit kinase inhibitor with anti-AML activity in vitro and in vivo. Further evaluation in toxicology and clinical studies is warranted.

Distinct Gene Mutations, their Prognostic Relevance and Molecularly Targeted Therapies in Acute Myeloid Leukemia (AML)

“…Small molecules such as SU5416 and SU6668 have activity against c-KIT [106] although neither is selective. A novel KIT inhibitor, APcK110 with potent proapoptotic and antiproliferative activity in AML cell lines and primary samples while in an AML xenograft mouse model it was found to extend survival [107]. In addition, KIT inhibition with dasatinib shows a promising approach to targeted therapy in t(8;21)AML and clinical trials are presently evaluating its clinical application.…”

Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2H-pyrazolo[4,3-c]pyridines

“…Pyrazolopyridines are among the most studied condensed pyrazole systems in organic and pharmaceutical chemistry (Figure 1). For instance, 6-(3,5-dimethoxyphenyl)-3-(4-fluorophenyl)-1H-pyrazolo [3,4-b]pyridine (APcK110) is an extensively researched Kit kinase inhibitor [32][33][34]. More recently, various 1H-pyrazolo [3,4b]pyridine derivatives were reported as potent ALK-L1196M [35] and CDK8 inhibitors [36], PPARα agonists [37], and antimicrobial, anti-quorum-sensing, and anticancer agents [38], while 3-amino-1H-pyrazolo [3,4-b]pyridine core was identified as a novel scaffold for MELK kinase inhibitors [39].…”