Best Practice & Research Clinical Endocrinology & Metabolism
4The molecular basis for RET tyrosine-kinase inhibitors in thyroid cancer
Section snippets
RET structure–function
RET (REarranged during Transfection) gene, named after its original identification through a NIH3T3 transfection assay, maps on the long arm of human chromosome 10 (10q11.21) and codes for a membrane receptor with tyrosine kinase activity (RTK) [1]. RET protein features a glycosylated extracellular (EC), a single pass transmembrane (TM), a juxtamembrane (JM), and an intracellular tyrosine kinase (TK) domain (Fig. 1). These are followed by two different carboxyl-terminal tails (C-tails), which
RET in human cancer
Germline activating RET mutations cause the autosomal dominant inheritance of Multiple Endocrine Neoplasia type 2 (MEN2A and MEN2B) syndromes [11]. These syndromes predispose to medullary thyroid carcinoma (MEN2A and MEN2B), pheochromocytoma (MEN2A and MEN2B), parathyroid hyperplasia (MEN2A only), and intestinal ganglioneuromatosis, corneal nerve thickening and marfanoid abitus (MEN2B only). Cutaneous lichen amyloidosis (CLA) and Hirschsprung's disease are rare phenotypes that can be found in
Small molecule tyrosine kinase inhibitors (TKIs)
A large number of TKIs (tyrosine kinase inhibitors) have entered preclinical and clinical development [27]. These drugs are small molecule organic compounds that bind, completely or partially, to the nucleotide binding pocket of the kinase domain, thus obstructing enzymatic activity. Depending on the spatial orientation of the activation loop, kinases can adopt active (so-called “DFG-in”, based on the position of the aspartate-phenylalanine-glycine [DFG] motif at the N-terminal of the
Clinically approved RET TKIs
Multi-kinase inhibitors with anti-RET activity have been approved for the treatment of thyroid or non thyroid cancers [23], [30]. These include vandetanib (for MTC) [31], [32], ∗[33], [34], cabozantinib (for MTC and renal cell carcinoma) [35], [36], ∗[37], [38], [39], lenvatinib (for differentiated thyroid carcinoma and renal cell carcinoma) [40], [41], ∗[42], [43], ponatinib (for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia) [44], [45], [46], [47],
Novel investigational TKIs with activity against RET
Several additional anti-RET compounds, belonging to different chemical classes, have been synthesized [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75]. In this section, we will focus on those compounds that have demonstrated, in protein- or cell-based assays, RET activity in the low nanomolar range and for which biochemical selectivity has been explored by enzymatic assays.
Main aim of SAR (structure–activity relationship) and medicinal chemistry efforts is to
Conclusions
Initially associated to medullary (MTC) and papillary (PTC) carcinomas of the thyroid gland, RET has been subsequently demonstrated to play an oncogenic driver role also in small fractions of several other malignancies. Multi-targeted TKIs, able to inhibit RET and VEGFR2, have been registered for the treatment of thyroid cancer or other malignancies (Table 1). Medicinal chemistry led to the identification of a set of new drugs with increased RET potency, selectivity, balanced RET/VEGFR2
Acknowledgements
This work has been supported by NIH grant 1R01CA197178-01A1R.
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