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Ref Type Journal Article
PMID (26046350)
Authors Moccia M, Liu Q, Guida T, Federico G, Brescia A, Zhao Z, Choi HG, Deng X, Tan L, Wang J, Billaud M, Gray NS, Carlomagno F, Santoro M
Title Identification of Novel Small Molecule Inhibitors of Oncogenic RET Kinase.
Journal PloS one
Vol 10
Issue 6
Date 2015
URL
Abstract Text Oncogenic mutation of the RET receptor tyrosine kinase is observed in several human malignancies. Here, we describe three novel type II RET tyrosine kinase inhibitors (TKI), ALW-II-41-27, XMD15-44 and HG-6-63-01, that inhibit the cellular activity of oncogenic RET mutants at two digit nanomolar concentration. These three compounds shared a 3-trifluoromethyl-4-methylpiperazinephenyl pharmacophore that stabilizes the 'DFG-out' inactive conformation of RET activation loop. They blocked RET-mediated signaling and proliferation with an IC50 in the nM range in fibroblasts transformed by the RET/C634R and RET/M918T oncogenes. They also inhibited autophosphorylation of several additional oncogenic RET-derived point mutants and chimeric oncogenes. At a concentration of 10 nM, ALW-II-41-27, XMD15-44 and HG-6-63-01 inhibited RET kinase and signaling in human thyroid cancer cell lines carrying oncogenic RET alleles; they also inhibited proliferation of cancer, but not non-tumoral Nthy-ori-3-1, thyroid cells, with an IC50 in the nM range. The three compounds were capable of inhibiting the 'gatekeeper' V804M mutant which confers substantial resistance to established RET inhibitors. In conclusion, we have identified a type II TKI scaffold, shared by ALW-II-41-27, XMD15-44 and HG-6-63-01, that may be used as novel lead for the development of novel agents for the treatment of cancers harboring oncogenic activation of RET.

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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
HG-6-63-01 HG-6-63-01 4 0
XMD15-44 XMD15-44 4 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
ALW-II-41-27 RET Inhibitor 39 ALW-II-41-27 is a small molecule that inhibits EPHA2 and RET, leading to decreased tumor cell proliferation and viability (PMID: 24713656, PMID: 26046350, PMID: 32848131).
HG-6-63-01 RET Inhibitor 39 HG-6-63-01 inhibits RET, resulting in decreased downstream signaling and reduced tumor cell proliferation (PMID: 26046350).
XMD15-44 RET Inhibitor 39 XMD15-44 inhibits RET, resulting in decreased downstream signaling and reduced tumor cell proliferation (PMID: 26046350).
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
RET M918T Advanced Solid Tumor sensitive ALW-II-41-27 Preclinical - Cell culture Actionable In a preclinical study, ALW-II-41-27 inhibited RET phosphorylation and downstream signaling, reduced proliferation of transformed cells expressing RET M918T in culture (PMID: 26046350). 26046350
RET M918T thyroid gland medullary carcinoma sensitive ALW-II-41-27 Preclinical - Cell culture Actionable In a preclinical study, ALW-II-41-27 inhibited RET phosphorylation and downstream signaling and reduced proliferation of medullary thryoid carcinoma cells harboring RET M918T in culture (PMID: 26046350). 26046350
RET M918T thyroid gland medullary carcinoma sensitive XMD15-44 Preclinical Actionable In a preclinical study, XMD15-44 inhibited RET phosphorylation and downstream signaling and reduced proliferation of medullary thyroid carcinoma cells harboring RET M918T in culture (PMID: 26046350). 26046350
RET C634Y Advanced Solid Tumor sensitive HG-6-63-01 Preclinical Actionable In a preclinical study, HG-6-63-01 inhibited RET phosphorylation and downstream signaling and reduced proliferation of transformed cells expressing RET C634Y in culture (PMID: 26046350). 26046350
RET C634W thyroid gland medullary carcinoma sensitive ALW-II-41-27 Preclinical - Cell culture Actionable In a preclinical study, ALW-II-41-27 inhibited RET phosphorylation and downstream signaling and reduced proliferation of medullary thyroid carcinoma cells harboring RET C634W in culture (PMID: 26046350). 26046350
RET C634W thyroid gland medullary carcinoma sensitive HG-6-63-01 Preclinical Actionable In a preclinical study, HG-6-63-01 inhibited RET phosphorylation and downstream signaling and reduced proliferation of medullary thyroid carcinoma cells harboring RET C634W in culture (PMID: 26046350). 26046350
RET C634W thyroid gland medullary carcinoma sensitive XMD15-44 Preclinical Actionable In a preclinical study, XMD15-44 inhibited RET phosphorylation and downstream signaling and reduced proliferation of medullary thyroid carcinoma cells harboring RET C634W in culture (PMID: 26046350). 26046350
RET C634Y Advanced Solid Tumor sensitive XMD15-44 Preclinical Actionable In a preclinical study, XMD15-44 inhibited RET phosphorylation and downstream signaling and reduced proliferation of transformed cells expressing RET C634Y in culture (PMID: 26046350). 26046350
RET M918T Advanced Solid Tumor sensitive HG-6-63-01 Preclinical Actionable In a preclinical study, HG-6-63-01 inhibited RET phosphorylation and downstream signaling and reduced proliferation of transformed cells expressing RET M918T in culture (PMID: 26046350). 26046350
RET M918T thyroid gland medullary carcinoma sensitive HG-6-63-01 Preclinical Actionable In a preclinical study, HG-6-63-01 inhibited RET phosphorylation and downstream signaling and reduced proliferation of medullary thyroid carcinoma cells harboring RET M918T in culture (PMID: 26046350). 26046350
RET M918T Advanced Solid Tumor sensitive XMD15-44 Preclinical Actionable In a preclinical study, XMD15-44 inhibited RET phosphorylation and downstream signaling and reduced proliferation of transformed cells expressing RET M918T in culture (PMID: 26046350). 26046350
RET C634Y Advanced Solid Tumor sensitive ALW-II-41-27 Preclinical - Cell culture Actionable In a preclinical study, ALW-II-41-27 inhibited RET phosphorylation and downstream signaling, reduced proliferation of transformed cells expressing RET C634Y in culture (PMID: 26046350). 26046350