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Ref Type Journal Article
PMID (40018846)
Authors Esdar C, Linde N, Blum A, Schieferstein H, Drechsler C, Sherbetjian E, Petersson C, Ross E, Leuthner B, Grädler U, Dorsch D, Blaukat A
Title M4205 (IDRX-42) Is a Highly Selective and Potent Inhibitor of Relevant Oncogenic Driver and Resistance Variants of KIT in Cancer.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 24 7 2025 Jul 02 1040-1053 Mol Cancer Ther
URL
Abstract Text Primary activating mutations in KIT (exon 9/11) are key driver alterations in about 80% of gastrointestinal stromal tumors (GIST). Imatinib, a small-molecule tyrosine kinase inhibitor, is used successfully as first-line therapy for patients with unresectable metastatic or recurrent GIST, but secondary resistance mutations in the KIT kinase domains frequently occur. Currently approved later-line therapies target these mutations incompletely with limited clinical benefit. M4205, a kinome-selective KIT inhibitor, was designed to address this high unmet medical need by inhibiting all relevant KIT driver and resistance mutations. Compared with imatinib, M4205 shows stronger antitumor activity in preclinical GIST models driven by oncogenic KIT driver mutations. M4205 demonstrates clinically relevant efficacy in a range of preclinical GIST models expressing different secondary KIT resistance mutations. The kinase selectivity profile of M4205 is superior to the registered standard of care and investigational agents. M4205, now IDRX-42, is currently being investigated in a phase I first-in-human study in participants with GIST.

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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
IDRX-42 IDRX-42 32 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
IDRX-42 M-4205|M 4205|M4205|IDRX 42|IDRX42 KIT Inhibitor 57 IDRX-42 is a KIT inhibitor, which potentially decreases tumor cell viability and reduces tumor growth (PMID: 40018846).
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
KIT W557_K558del gastrointestinal stromal tumor predicted - sensitive Imatinib Preclinical - Pdx Actionable In a preclinical study, Gleevec (imatinib) induced tumor regression in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT W557_K558del (PMID: 40018846). 40018846
KIT V560_Y578del KIT V654A gastrointestinal stromal tumor sensitive Sunitinib Preclinical - Cell line xenograft Actionable In a preclinical study, Sutent (sunitinib) induced stasis in a cell line xenograft model of gastrointestinal stromal tumor harboring KIT V560_Y578del and KIT V654A (PMID: 40018846). 40018846
KIT V560_Y578del KIT V654A gastrointestinal stromal tumor resistant Avapritinib Preclinical - Cell line xenograft Actionable In a preclinical study, Ayvakit (avapritinib) treatment failed to inhibit tumor growth in a cell line xenograft model of gastrointestinal stromal tumor harboring KIT V560_Y578del and KIT V654A (PMID: 40018846). 40018846
KIT V560_Y578del KIT V654A gastrointestinal stromal tumor predicted - resistant Ripretinib Preclinical - Cell line xenograft Actionable In a preclinical study, Qinlock (ripretinib) treatment failed to inhibit tumor growth in a cell line xenograft model of gastrointestinal stromal tumor harboring KIT V560_Y578del and KIT V654A (PMID: 40018846). 40018846
KIT V559D KIT T670I Advanced Solid Tumor predicted - sensitive IDRX-42 Preclinical - Biochemical Actionable In a preclinical study, IDRX-42 inhibited kinase activity of KIT V559D and KIT T670I in an vitro assay (PMID: 40018846). 40018846
KIT W557_K558del KIT Y823D gastrointestinal stromal tumor sensitive IDRX-42 Preclinical - Pdx Actionable In a preclinical study, IDRX-42 treatment resulted in tumor shrinkage in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT W557_K558del and KIT Y823D (PMID: 40018846). 40018846
KIT V560G Advanced Solid Tumor predicted - sensitive IDRX-42 Preclinical - Biochemical Actionable In a preclinical study, IDRX-42 inhibited kinase activity of KIT V560G in an vitro assay (PMID: 40018846). 40018846
KIT N822K acute myeloid leukemia sensitive IDRX-42 Preclinical - Cell line xenograft Actionable In a preclinical study, IDRX-42 inhibited viability of an acute myeloid leukemia cell line harboring KIT N822K in culture, and induced tumor regression in a cell line xenograft model (PMID: 40018846). 40018846
KIT V560_Y578del KIT V654A gastrointestinal stromal tumor resistant Regorafenib Preclinical - Cell line xenograft Actionable In a preclinical study, Stivarga (regorafenib) treatment failed to inhibit tumor growth in a cell line xenograft model of gastrointestinal stromal tumor harboring KIT V560_Y578del and KIT V654A (PMID: 40018846). 40018846
KIT W557_K558del Advanced Solid Tumor predicted - sensitive IDRX-42 Preclinical - Biochemical Actionable In a preclinical study, IDRX-42 inhibited kinase activity of KIT W557_K558del in an vitro assay (PMID: 40018846). 40018846
KIT W557_V559delinsF gastrointestinal stromal tumor sensitive IDRX-42 Preclinical - Pdx & cell culture Actionable In a preclinical study, IDRX-42 inhibited viability of a gastrointestinal stromal tumor cell line harboring KIT W557_V559delinsF in culture, and induced tumor regression in a patient-derived xenograft (PDX) model (PMID: 40018846). 40018846
KIT V560G KIT N822K Advanced Solid Tumor predicted - sensitive IDRX-42 Preclinical - Biochemical Actionable In a preclinical study, IDRX-42 inhibited kinase activity of KIT V560G and KIT N822K in an vitro assay (PMID: 40018846). 40018846
FLT3 exon 14 ins acute myeloid leukemia sensitive IDRX-42 Preclinical - Cell culture Actionable In a preclinical study, IDRX-42 inhibited viability of acute myeloid leukemia cell lines harboring FLT3-ITD in culture (PMID: 40018846). 40018846
KIT V559D Advanced Solid Tumor predicted - sensitive IDRX-42 Preclinical - Biochemical Actionable In a preclinical study, IDRX-42 inhibited kinase activity of KIT V559D in an vitro assay (PMID: 40018846). 40018846
KIT K642E Advanced Solid Tumor predicted - sensitive IDRX-42 Preclinical - Biochemical Actionable In a preclinical study, IDRX-42 inhibited kinase activity of KIT K642E in an vitro assay (PMID: 40018846). 40018846
KIT V559D KIT V654A Advanced Solid Tumor predicted - sensitive IDRX-42 Preclinical - Biochemical Actionable In a preclinical study, IDRX-42 inhibited kinase activity of KIT V559D and KIT V654A in an vitro assay (PMID: 40018846). 40018846
KIT D816V Advanced Solid Tumor predicted - sensitive IDRX-42 Preclinical - Biochemical Actionable In a preclinical study, IDRX-42 inhibited kinase activity of KIT D816V in an vitro assay (PMID: 40018846). 40018846
KIT V560G KIT D816V Advanced Solid Tumor predicted - sensitive IDRX-42 Preclinical - Biochemical Actionable In a preclinical study, IDRX-42 inhibited kinase activity of KIT V560G and KIT D816V in an vitro assay (PMID: 40018846). 40018846
KIT D816E Advanced Solid Tumor predicted - sensitive IDRX-42 Preclinical - Biochemical Actionable In a preclinical study, IDRX-42 inhibited kinase activity of KIT D816E in an vitro assay (PMID: 40018846). 40018846
KIT V559A Advanced Solid Tumor predicted - sensitive IDRX-42 Preclinical - Biochemical Actionable In a preclinical study, IDRX-42 inhibited kinase activity of KIT V559A in an vitro assay (PMID: 40018846). 40018846
KIT T670I Advanced Solid Tumor predicted - sensitive IDRX-42 Preclinical - Biochemical Actionable In a preclinical study, IDRX-42 inhibited kinase activity of KIT T670I in an vitro assay (PMID: 40018846). 40018846
KIT V560_Y578del KIT V654A gastrointestinal stromal tumor resistant Imatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Gleevec (imatinib) treatment did not inhibit tumor growth in a cell line xenograft model of gastrointestinal stromal tumor harboring KIT V560_Y578del and KIT V654A (PMID: 40018846). 40018846
KIT W557_K558del KIT V654A gastrointestinal stromal tumor sensitive Sunitinib Preclinical - Cell line xenograft Actionable In a preclinical study, Sutent (sunitinib) induced tumor stasis in a cell line xenograft model of gastrointestinal stromal tumor harboring KIT W557_K558del and KIT V654A (PMID: 40018846). 40018846
KIT D816F Advanced Solid Tumor predicted - sensitive IDRX-42 Preclinical - Biochemical Actionable In a preclinical study, IDRX-42 inhibited kinase activity of KIT D816F in an vitro assay (PMID: 40018846). 40018846
KIT D820Y Advanced Solid Tumor predicted - sensitive IDRX-42 Preclinical - Biochemical Actionable In a preclinical study, IDRX-42 inhibited kinase activity of KIT D820Y in an vitro assay (PMID: 40018846). 40018846
KIT W557_K558del KIT Y823D gastrointestinal stromal tumor predicted - sensitive Sunitinib Preclinical - Cell line xenograft Actionable In a preclinical study, Sutent (sunitinib) induced tumor stasis in a cell line xenograft model of gastrointestinal stromal tumor harboring KIT W557_K558del and KIT Y823D (PMID: 40018846). 40018846
KIT A829P Advanced Solid Tumor predicted - sensitive IDRX-42 Preclinical - Biochemical Actionable In a preclinical study, IDRX-42 inhibited kinase activity of KIT A829P in an vitro assay (PMID: 40018846). 40018846
KIT V560_Y578del KIT V654A gastrointestinal stromal tumor sensitive IDRX-42 Preclinical - Pdx & cell culture Actionable In a preclinical study, IDRX-42 inhibited viability of a gastrointestinal stromal tumor cell line harboring KIT V560_Y578del and KIT V654A in culture, and resulted in tumor shrinkage in a cell line xenograft model and a complete response in a patient-derived xenograft (PDX) model (PMID: 40018846). 40018846
KIT V560_Y578del gastrointestinal stromal tumor sensitive IDRX-42 Preclinical - Cell line xenograft Actionable In a preclinical study, IDRX-42 inhibited viability of a gastrointestinal stromal tumor cell line harboring KIT V560_Y578del in culture, and induced tumor regression in a cell line xenograft model (PMID: 40018846). 40018846
KIT W557_K558del KIT V654A gastrointestinal stromal tumor sensitive IDRX-42 Preclinical - Pdx Actionable In a preclinical study, IDRX-42 treatment led to a complete response in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT W557_K558del and KIT V654A (PMID: 40018846). 40018846
KIT D816I Advanced Solid Tumor predicted - sensitive IDRX-42 Preclinical - Biochemical Actionable In a preclinical study, IDRX-42 inhibited kinase activity of KIT D816I in an vitro assay (PMID: 40018846). 40018846
KIT W557_K558del gastrointestinal stromal tumor sensitive IDRX-42 Preclinical - Pdx Actionable In a preclinical study, IDRX-42 induced tumor regression in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT W557_K558del (PMID: 40018846). 40018846
KIT Y823D Advanced Solid Tumor predicted - sensitive IDRX-42 Preclinical - Biochemical Actionable In a preclinical study, IDRX-42 inhibited kinase activity of KIT Y823D in an vitro assay (PMID: 40018846). 40018846
KIT D820E Advanced Solid Tumor predicted - sensitive IDRX-42 Preclinical - Biochemical Actionable In a preclinical study, IDRX-42 inhibited kinase activity of KIT D820E in an vitro assay (PMID: 40018846). 40018846
KIT V654A Advanced Solid Tumor predicted - sensitive IDRX-42 Preclinical - Biochemical Actionable In a preclinical study, IDRX-42 inhibited kinase activity of KIT V654A in an vitro assay (PMID: 40018846). 40018846
KIT W557_K558del KIT Y823D gastrointestinal stromal tumor sensitive Ripretinib Preclinical - Pdx Actionable In a preclinical study, Qinlock (ripretinib) inhibited tumor growth in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT W557_K558del and KIT Y823D (PMID: 40018846). 40018846