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Ref Type Journal Article
PMID (38007585)
Authors Tyagi A, Jaggupilli A, Ly S, Yuan B, El-Dana F, Hegde VL, Anand V, Kumar B, Puppala M, Yin Z, Wong STC, Mollard A, Vankayalapati H, Foulks JM, Warner SL, Daver N, Borthakur G, Battula VL
Title TP-0184 inhibits FLT3/ACVR1 to overcome FLT3 inhibitor resistance and hinder AML growth synergistically with venetoclax.
Abstract Text We identified activin A receptor type I (ACVR1), a member of the TGF-β superfamily, as a factor favoring acute myeloid leukemia (AML) growth and a new potential therapeutic target. ACVR1 is overexpressed in FLT3-mutated AML and inhibition of ACVR1 expression sensitized AML cells to FLT3 inhibitors. We developed a novel ACVR1 inhibitor, TP-0184, which selectively caused growth arrest in FLT3-mutated AML cell lines. Molecular docking and in vitro kinase assays revealed that TP-0184 binds to both ACVR1 and FLT3 with high affinity and inhibits FLT3/ACVR1 downstream signaling. Treatment with TP-0184 or in combination with BCL2 inhibitor, venetoclax dramatically inhibited leukemia growth in FLT3-mutated AML cell lines and patient-derived xenograft models in a dose-dependent manner. These findings suggest that ACVR1 is a novel biomarker and plays a role in AML resistance to FLT3 inhibitors and that FLT3/ACVR1 dual inhibitor TP-0184 is a novel potential therapeutic tool for AML with FLT3 mutations.


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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
TP-0184 TP-0184 1 2
Drug Name Trade Name Synonyms Drug Classes Drug Description
TP-0184 TP0184|TP 0184|itacnosertib FLT3 Inhibitor 66 TP-0184 inhibits ACVR1 and FLT3 and reduces downstream signaling, potentially resulting in decreased tumor cell proliferation and inhibition of tumor growth (PMID: 38007585).
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
FLT3 exon 14 ins acute myeloid leukemia sensitive TP-0184 + Venetoclax Preclinical - Cell culture Actionable In a preclinical study, the combination of TP-0184 and Venclexta (venetoclax) synergistically inhibited proliferation of acute myeloid leukemia cells harboring a FLT3-ITD in culture, and inhibited tumor growth and prolonged survival in a cell line xenograft model (PMID: 38007585). 38007585
FLT3 exon 14 ins acute myeloid leukemia sensitive TP-0184 Preclinical - Pdx & cell culture Actionable In a preclinical study, TP-0184 inhibited proliferation and growth of acute myeloid leukemia cells harboring a FLT3-ITD mutation in culture, and inhibited tumor growth and improved survival in cell line and patient-derived xenograft models (PMID: 38007585). 38007585