Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
PloS one	10	6	2015	e0128364	PLoS One

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
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence
ALW-II-41-27	ALW-II-41-27	4
HG-6-63-01	HG-6-63-01	4
XMD15-44	XMD15-44	4

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Drug Name	Drug Classes	Drug Description
ALW-II-41-27	RET Inhibitor 53	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 53	HG-6-63-01 inhibits RET, resulting in decreased downstream signaling and reduced tumor cell proliferation (PMID: 26046350).
XMD15-44	RET Inhibitor 53	XMD15-44 inhibits RET, resulting in decreased downstream signaling and reduced tumor cell proliferation (PMID: 26046350).

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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RET C634W	medullary thyroid 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 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
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	medullary thyroid 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 C634W	medullary thyroid 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 C634W	medullary thyroid 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 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 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	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 M918T	medullary thyroid 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 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	medullary thyroid 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

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