Challenging clinically unresponsive medullary thyroid cancer: Discovery and pharmacological activity of novel RET inhibitors

Eur J Med Chem. 2018 Apr 25;150:491-505. doi: 10.1016/j.ejmech.2018.02.080. Epub 2018 Mar 2.

Abstract

It is now known that "gain of function" mutations of RET (REarranged during Transfection) kinase are specific and key oncogenic events in the onset of thyroid gland cancers such as the Medullary Thyroid Carcinoma (MTC). Although a number of RET inhibitors exist and are capable of inhibiting RET variants, in which mutations are outside the enzyme active site, the majority becomes dramatically ineffective when mutations are within the protein active site (V804L and V804M). Pursuing a receptor-based virtual screening against the kinase domain of RET, we found that compound 5 is able to inhibit efficiently both wild type and V804L mutant RET. Compound 5 was able to significantly reduce proliferation of both commercially available TT cell lines and surgical thyroid tissues obtained from patients with MTC and displayed a suitable drug-like profile, thus standing out as a promising candidate for further development towards the treatment of clinically unresponsive MTC.

Keywords: Docking; Focused library; Medullary thyroid carcinoma; RET kinase; Virtual screening.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Neuroendocrine / drug therapy*
  • Carcinoma, Neuroendocrine / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-ret / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-ret / genetics
  • Proto-Oncogene Proteins c-ret / metabolism
  • Structure-Activity Relationship
  • Thyroid Gland / drug effects*
  • Thyroid Gland / metabolism
  • Thyroid Gland / pathology
  • Thyroid Neoplasms / drug therapy*
  • Thyroid Neoplasms / metabolism

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-ret
  • RET protein, human

Supplementary concepts

  • Thyroid cancer, medullary