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Ref Type Journal Article
PMID (37392657)
Authors Choi YJ, Park J, Choi H, Oh SJ, Park JH, Park M, Kim JW, Kim YG, Kim YC, Kim MJ, Kang KW
Title PLM-101 is a novel and potent FLT3/RET inhibitor with less adverse effects in the treatment of acute myeloid leukemia.
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Abstract Text Acute myeloid leukemia (AML) is a prevalent form of leukemia in adults. As its survival rate is low, there is an urgent need for new therapeutic options. In AML, FMS-like tyrosine kinase 3 (FLT3) mutations are common and have negative outcomes. However, current FLT3-targeting agents, Midostaurin and Gilteritinib, face two significant issues, specifically the emergence of acquired resistance and drug-related adverse events leading to treatment failure. Rearranged during transfection (RET), meanwhile, is a proto-oncogene linked to various types of cancer, but its role in AML has been limited. A previous study showed that activation of RET kinase enhances FLT3 protein stability, leading to the promotion of AML cell proliferation. However, no drugs are currently available that target both FLT3 and RET. This study introduces PLM-101, a new therapeutic option derived from the traditional Chinese medicine indigo naturalis with potent in vitro and in vivo anti-leukemic activities. PLM-101 potently inhibits FLT3 kinase and induces its autophagic degradation via RET inhibition, providing a superior mechanism to that of FLT3 single-targeting agents. Single- and repeated-dose toxicity tests conducted in the present study showed no significant drug-related adverse effects. This study is the first to present a new FLT3/RET dual-targeting inhibitor, PLM-101, that shows potent anti-leukemic activity and fewer adverse effects. PLM-101, therefore, should be considered for use as a potential therapeutic agent for AML.

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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
PLM-101 PLM-101 4 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
PLM-101 PLM101|PLM 101 FLT3 Antibody 5 RET Inhibitor 52 PLM-101 inhibits FLT3 and RET, potentially resulting increased cell cycle arrest and apoptosis and decreased tumor growth (PMID: 37392657).
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 FLT3 F691L hematologic cancer sensitive PLM-101 Preclinical - Cell culture Actionable In a preclinical study, PLM-101 inhibited proliferation in cells expressing FLT3 F691L in the context of a FLT3-ITD mutation in culture (PMID: 37392657). 37392657
FLT3 exon 14 ins hematologic cancer sensitive PLM-101 Preclinical - Cell culture Actionable In a preclinical study, PLM-101 inhibited kinase activity and proliferation in cells expressing a FLT3-ITD mutation in culture (PMID: 37392657). 37392657
FLT3 exon 14 ins acute myeloid leukemia sensitive PLM-101 Preclinical - Cell line xenograft Actionable In a preclinical study, PLM-101 induced apoptosis and cell cycle arrest and inhibited Flt3 phosphorylation, downstream signaling, and proliferation in acute myeloid leukemia cell lines harboring a FLT3-ITD mutation in culture and inhibited tumor growth in cell line xenograft models (PMID: 37392657). 37392657
FLT3 exon 14 ins FLT3 D835Y hematologic cancer sensitive PLM-101 Preclinical - Cell culture Actionable In a preclinical study, PLM-101 inhibited proliferation in cells expressing FLT3 D835Y in the context of a FLT3-ITD mutation in culture (PMID: 37392657). 37392657