A Pyrazolo[3,4-D]pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants

Hojong Yoon, Yeonui Kwak, Seunghye Choi, Hanna Cho, Nam Doo Kim, Taebo Sim

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Aberrant RET kinase signaling plays critical roles in several human cancers such as thyroid carcinoma. The gatekeeper mutants (V804L or V804M) of RET are resistant to currently approved RET inhibitors such as cabozantinib and vandetanib. We, for the first time, report a highly selective and extremely potent RET inhibitor, 6i rationally designed. Compound 6i inhibits strongly RET gatekeeper mutants and other clinically relevant RET mutants as well as wt-RET. This substance also significantly suppresses growth of thyroid cancer-derived TT cell lines and Ba/F3 cells transformed with various RET mutants. Docking studies reveal that the isoxazole moiety in 6i is responsible for binding affinity improvement by providing additional site for H-bonding with Lys758. Also, 6i not only substantially blocks cellular RET autophosphorylation and its downstream pathway, it markedly induces apoptosis and anchorage-independent growth inhibition in TT cell lines while having no effect on normal thyroid Nthy ori-3-1 cells.

Original languageEnglish
Pages (from-to)358-373
Number of pages16
JournalJournal of Medicinal Chemistry
Volume59
Issue number1
DOIs
Publication statusPublished - 2016 Jan 14

Fingerprint

Isoxazoles
Thyroid Neoplasms
Amines
Cell Line
Growth
Thyroid Gland
Phosphotransferases
Apoptosis
Neoplasms
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine
cabozantinib

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

A Pyrazolo[3,4-D]pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants. / Yoon, Hojong; Kwak, Yeonui; Choi, Seunghye; Cho, Hanna; Kim, Nam Doo; Sim, Taebo.

In: Journal of Medicinal Chemistry, Vol. 59, No. 1, 14.01.2016, p. 358-373.

Research output: Contribution to journalArticle

Yoon, Hojong ; Kwak, Yeonui ; Choi, Seunghye ; Cho, Hanna ; Kim, Nam Doo ; Sim, Taebo. / A Pyrazolo[3,4-D]pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 1. pp. 358-373.
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