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

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.

Updates on the Management of Thyroid Cancer

“…As with other TKIs, the anti-tumor activity of these two drugs stems from their ability to simultaneously inhibit multiple, but functionally related kinases which would result in disruption of their associated pathways both in the parenchymal and stromal components of the thyroid gland [80]. The kinases inhibited by these drugs are: RET, VEGFR, EGFR for vandetanib, and RET, VEGFR, c-KIT and MET for cabozantinib [80]. However, therapy with TKIs is associated with significant adverse effects most likely due to wide-spread inhibition of RET at 'off-target' sites.…”

“…However, therapy with TKIs is associated with significant adverse effects most likely due to wide-spread inhibition of RET at 'off-target' sites. Moreover, certain forms of RET disease-causing variants that affect the active enzymatic site of RET, such as V804L and V804M variants, can render all of the currently known non-specific RET inhibitors ineffective in treating MTC [80]. In fact, the V804 residue in the RET backbone also corresponds to the gate-keeper position of several other kinases, including c-KIT, EGFR, PDGFR, and Abl [80].…”

“…Moreover, certain forms of RET disease-causing variants that affect the active enzymatic site of RET, such as V804L and V804M variants, can render all of the currently known non-specific RET inhibitors ineffective in treating MTC [80]. In fact, the V804 residue in the RET backbone also corresponds to the gate-keeper position of several other kinases, including c-KIT, EGFR, PDGFR, and Abl [80]. Therefore, utilization of novel small molecules that selectively target RET rather than multiple kinases has been investigated in phase 2 clinical trials.…”

Receptor‐guided 3D‐QSAR Study of Anilinoquinazolines as RET Receptor Tyrosine Kinase Antagonists

“…Several RET antagonists have progressed as plausible agents against cancer. Recently FDA and EMA have approved vandetanib, cabozantinib, sorafenib, and lenvatinib for the treatment of MTC. But, these inhibitors are non‐selective to RET and possess elevated efficacy against some other protein kinases .…”

“…Few computational studies on RET kinase inhibitors have been reported. In a recent study, Pietra et al ., reported the discovery of novel RET inhibitors using receptor‐based virtual screening . He reported a new antagonist, 5‐(4‐chlorophenyl)‐3‐((4‐chlorophenylthio)methyl)‐1H‐1,2,4‐triazole, that showed to inhibit efficiently wild‐type and V804L mutant RET kinase as well .…”