Abstract
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.
Highlights
The REarranged during Transfection (RET) gene codes for a single pass transmembrane tyrosine kinase (TK) receptor that is mutated in several human cancers [1]
RET oncogenic conversion is a hallmark of several human cancers, including papillary and medullary thyroid carcinoma, lung adenocarcinoma and chronic myelomonocytic leukemia
This screening resulted in the identification of ALW-II-41-27, XMD15-44, and HG-6-63-01 as novel and potent RET tyrosine kinase inhibitors (TKI)
Summary
The REarranged during Transfection (RET) gene codes for a single pass transmembrane tyrosine kinase (TK) receptor that is mutated in several human cancers [1]. In approximately 20% of human papillary thyroid carcinoma (PTC), RET exons encoding the tyrosine kinase domain. Missense germline and somatic point mutations of RET are associated to familial (95%) and sporadic (50%) cases of medullary thyroid carcinoma (MTC), respectively. MTC associated RET mutations commonly target cysteine residues in the extracellular domain or the intracellular tyrosine kinase domain [1,2,3]. In roughly 1% of non small cell lung cancers (NSCLC), in adenocarcinoma, chromosomal inversions cause the fusion of the RET-encoded TK domain to different exons of KIF5B (kinesin family member 5B) gene or, less commonly, to CCDC6, NCOA4 or TRIMM33 [4,5,6,7,8]. In patients affected by myeloproliferative disorders (MPD), such as chronic myelomonocytic leukemia or primary myelofibrosis, oncogenic RET fusions with BCR or FGFR1OP genes were identified [9, 10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
