Development of RET Kinase Inhibitors for Targeted Cancer Therapy

L.      Mologni

Abstract

RET (Rearranged during Transfection) is a transmembrane tyrosine kinase expressed in central and peripheral nervous system and neural crest-derived cells and acts as a co-receptor of GDNF family neurotrophic factor in complex with GRFα family proteins. RET protein comprises an extracellular portion with four cadherine-like domains and a cysteine- rich region important for intermolecular interactions; a hydrophobic transmembrane domain; an intracellular part comprising the juxtamembrane domain with regulatory function and the catalytic domain that phosphorylates the tyrosine residues of substrates. RET is involved in the development of enteric nervous system and renal organogenesis during embryonic life. Mutations of RET are associated to a subset of colorectal cancer and are commonly found in hereditary and sporadic thyroid cancer. Activating point mutations in the cystein-rich or the kinase domain of RET cause multiple endocrine neoplasia type 2 (MEN2), a group of familial cancer syndromes characterized by medullary thyroid carcinoma, pheochromocytoma, parathyroid hyperplasia and ganglioneuromatosis of the gastroenteric mucosa. Rearranged forms of RET (termed RET/PTC) are detected in the majority of papillary thyroid carcinomas (PTC). At present, the therapeutic treatment available for these pathologies is the total or partial surgical removal of thyroid, associated with radio-iodine therapy or chemotherapy: despite widespread use of multimodality treatment, survival rates have not improved much in the past few decades, which suggests that new treatment options should be explored. Several small-molecule inhibitors of RET kinase activity have been described in the last decade, some of which are currently undergoing clinical evaluation. Here, I review the large preclinical effort to the development of specific RET inhibitors, including medicinal chemistry analyses that may help refine potency and selectivity of future RET-targeted inhibitors.

Keywords: RET, tyrosine kinase, small-molecule inhibitor, thyroid cancer, PTC, target therapy, Rearranged during Transfection, renal organogenesis, colorectal cancer, medullary thyroid carcinoma, pheochromocy-toma, parathyroid hyperplasia, ganglioneuromatosis, gastroenteric mucosa, papillary thyroid carcinomas, cytotoxic agents, homeostasis, oncogenic factors, oncogene addiction, chronic myeloid leukemia, glial-derived neurotrophic factor, tyrosine residues (Tyr), spermatogonia, Hirsch-prung's disease, C-heli, multiple endocrine neoplasia (MEN), somatic mutations, lung carcinoma, heat shock protein 90 (Hsp90), herbimycin A, geldanamycin, genistein, imatinib, Staurosporine, pyrazolo-pyrimidine, valine, proteasome, quinazoline, autophosphorylation, bromofluorophenyl, methionine, methylpiperidin-methoxy, oxindole, quantitative analysis, Sorafenib, xenografts growth, Motesanib, Fostamatinib, spleen tyrosine kinase