The Wnt/β-catenin signaling pathway plays a pivotal role in numerous biological processes and its dysregulation has been implicated in diverse oncolytic initiation. Aberrant overactivation of the Wnt/β-catenin pathway due to overexpression and accumulation of the β-catenin has been often observed in colorectal cancer (CRC). As a member of PARP family (PARP5 isoform), tankyrase (TNKS) regulates stability of the β-catenin destruction complex through Axin poly-ADP ribosylation maintaining homeostasis of level of the β-catenin. Axin is a rate-limiting component of the destruction complex and inhibition of tankyrase stabilizes Axin level to prevent subsequently CRC development by downregulation of the Wnt target genes. We herein report an orally-active tankyrase inhibitor STP06-1002 with excellent cellular potency, good ADME properties, and in vivo anti-tumor efficacy with moderate safety.
The novel tankyrase inhibitor STP06-1002 shows good inhibition activities with IC50 29.9 nM (TNKS1) and 3.7 nM (TNKS2) and its excellent cellular potency with IC50 6.7 nM (TCF/LEF). STP06-1002 also shows excellent selectivity against PARP1 isoform with IC50 >10 μM. STP06-1002 has good ADME properties, particularly low CYP450 inhibition & induction in CYP3A and PXR, suggesting no DDI issues. It also displays good in vivo pharmacokinetic profiles in rats (B.A. [F] >60%) and dogs (27%). No significant toxicity issues are observed from cytotoxicity studies, hERG assay and Ames test. The off-target studies in both Pan Kinase panel (against 75 cancer-focused kinases) and Lead Profiling Screen® (against 68 receptors and ion channels) prove its high selectivity. In the xenograft efficacy studies for in vivo proof-of-concept, the dose-dependent effect on Colo320DM (Wnt-dependent, KRas wild type) shows tumor growth inhibition with 45% and DLD-1 (Wnt-dependent, KRas mutant) with 60%. In the case of Wnt-independent cell lines HCT116 and RKO as negative controls, both did not show any tumor growth inhibition effects. Dose range finding study of rodent (rat) resulted in maximum tolerated dose of (MTD) 200 mg/kg/day, and the corresponding of non-rodent (dog) MTD of 30 mg/kg/day. Taking these promising preclinical results of optimal in vivo efficacy dose, MTD and HSTD (50 mg/kg/day) into account, we suggest safety margin of the STP06-1002 as 6 to 11 folds applicable to clinical human dosages.
The preclinical studies of STP06-1002 show successfully its potentials as an anticancer therapeutic agent. Based on the excellent biological and preclinical profiles, STP06-1002 will be a suitable candidate as an orally-active novel TNKS inhibitor and move toward phase I clinical trials with strong biomarker-based strategies.
Citation Format: Kyungjin Kim, Uk-Il Kim, Hyung Tae Bang, Jihye Yoon, Jin Ha Hwang, Jung-Nyoung Heo, Kwang-Rok Kim, Hwan Jung Lim, Jai-Hee Moon, Eun Young Lee, Seul Lee, Dong-Hoon Jin. Design and development of a tankyrase inhibitor STP06-1002 as an anticancer therapeutic agent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5171. doi:10.1158/1538-7445.AM2017-5171