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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 European journal of cancer (Oxford, England : 1990)
Vol 173
Issue
Date 2022 Jul 15
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 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 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 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 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
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