Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie	165		2023 Sep	115066	Biomed Pharmacother

URL

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 53	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 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
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	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