Reference Detail

Ref Type

Journal Article

PMID

(35849876)

Authors

Kim DY, Kwon YJ, Seo WY, Kim UI, Ahn S, Choi SM, Bang HT, Kim K, Kim JS

Title

Tankyrase-selective inhibitor STP1002 shows preclinical antitumour efficacy without on-target toxicity in the gastrointestinal tract.

Journal	Vol	Issue	Date	Pages	Journal Short Title
European journal of cancer (Oxford, England : 1990)	173		2022 Jul 15	41-51	Eur J Cancer

URL

Abstract Text

Tankyrase inhibition stabilises AXINs and antagonises the Wnt/β-catenin pathway in adenomatous polyposis coli (APC)-mutated colorectal cancer (CRC), suggesting that tankyrase is a potential therapeutic target for APC-mutated CRC. However, clinical trials on reported tankyrase inhibitors have been severely limited by on-target toxicity in the gastrointestinal (GI) tract. Herein, we report a new tankyrase-selective inhibitor, STP1002, having preclinical antitumour efficacy without on-target toxicity in APC-mutated CRC models.STP1002 was developed and characterised using in vitro and in vivo functional studies; its pharmacokinetics, antitumour efficacy and toxicity were evaluated in vivo.STP1002 showed potent, selective inhibition of tankyrase 1/2 but not of members of the poly (ADP-ribose) polymerase 1/2 (PARP1/2). STP1002 exerted antitumour activity by stabilising AXINs and antagonising the Wnt/β-catenin pathway in a subset of APC-mutated CRC cell lines but not in inhibitor-resistant cells and APC-wild-type CRC cell lines. STP1002 showed favourable pharmacokinetic profiles for oral administration once daily. STP1002 inhibited tumour growth of APC-mutated CRC xenograft animal models but not of APC-wild type models in a dose-dependent manner. The antitumour efficacy of STP1002 was confirmed using APC-mutated CRC patient-derived tumour xenograft models. STP1002 showed no significant on-target toxicity in the GI tract compared to G007-LK, which shows severe ileum toxicity in preclinical animal models.These results demonstrate that STP1002, a novel, orally active tankyrase inhibitor, shows preclinical antitumour efficacy without on-target toxicity in the GI tract. Our data provide a rationale for a clinical trial on STP1002 as a potential tankyrase-targeted drug in patients with APC-mutated CRC.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
STP1002	STP1002	5	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
STP1002		STP 1002\|STP-1002	Tankyrase Inhibitor 11	STP1002 binds to and inhibits Tankyrase, which results in stabilization of AXIN and decreased Wnt/beta-catenin signaling, potentially leading to decreased cell proliferation and tumor growth (PMID: 35849876).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
APC Q1338*	colorectal cancer	sensitive	STP1002	Preclinical - Cell culture	Actionable	In a preclinical study, STP1002 inhibited Wnt/beta-catenin signaling and colony formation in colorectal cancer cell lines harboring APC Q1338* in culture (PMID: 35849876).	35849876
APC E1309Dfs*4	colorectal cancer	sensitive	STP1002	Preclinical - Cell culture	Actionable	In a preclinical study, STP1002 inhibited Wnt/beta-catenin signaling and colony formation in a colorectal cancer cell line harboring APC E1309Dfs*4 in culture (PMID: 35849876).	35849876
APC S811*	colorectal cancer	sensitive	STP1002	Preclinical - Cell line xenograft	Actionable	In a preclinical study, STP1002 inhibited Wnt/beta-catenin signaling and colony formation in colorectal cancer cell lines harboring APC S811* in culture and inhibited tumor growth in a cell line xenograft model (PMID: 35849876).	35849876
APC R1450*	colorectal cancer	sensitive	STP1002	Preclinical - Pdx	Actionable	In a preclinical study, STP1002 inhibited tumor growth in a colorectal cancer patient-derived xenograft (PDX) model harboring APC R1450* (PMID: 35849876).	35849876
APC E853* APC T1556Nfs*3	colorectal cancer	sensitive	STP1002	Preclinical - Cell culture	Actionable	In a preclinical study, STP1002 inhibited Wnt/beta-catenin signaling and colony formation in a colorectal cancer cell line harboring APC E853* and APC T1556Nfs*3 in culture (PMID: 35849876).	35849876