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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.
Journal Vol Issue Date Pages Journal Short Title
Leukemia 2023 Nov 25 Leukemia
URL
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 69 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