Study identifies cryptic oncoprotein vulnerabilities for cancer drug development
RET is a receptor protein with tyrosine kinase activity that can transfer a phosphate group from ATP to other molecules changing their shape and function in signaling pathways essential for organogenesis and tissue maintenance. Genetic gain-of-function alterations in RET, for example point mutations or chromosomal rearrangements that produce oncogenic fusions, are implicated in certain types of cancer, particularly those of the thyroid, and less commonly, lung and breast cancers, among others. Current cancer therapies against RET-induced tumors are based on ATP-competitive inhibitors of RET catalytic activity. Second-generation inhibitors, which include LOXO-292 (selpercatinib) and BLU-667 (pralsetinib), have been approved by the FDA and are showing remarkable clinical responses in cancer patients.
The Kinases, Protein Phosphorylation and Cancer group of the Spanish National Cancer Research Center (CNIO), led by Ivan Plaza Menacho, has successfully identified the structural and dynamic features exploited by these inhibitors, and in particular a cryptic pocket within of the active site which confers a high specificity for these compounds. “The crystal structure of the RET catalytic domain in complex with these inhibitors has already been resolved, but the cryptic pockets of the active site have not been identified, as they are not always accessible due to the dynamical and conformational changes that the crystal structure don’t capture,” remarks Plaza-Menacho.
The Kinases, Protein Phosphorylation and Cancer group focuses on the detailed structural and functional characterization of a family of proteins called kinases involved in cancer. This information can be translated into the design of better compounds and inhibitors that will result in improved therapies. “Second-generation RET inhibitors, which were recently approved by the FDA to treat RET-induced thyroid and lung cancers, bind to the active site in an unusual way compared to prototypical RET inhibitors. , we didn’t fully understand why they were so effective,” adds Plaza-Menacho.
Currently, the group led by Plaza-Menacho is working closely with the CNIO’s Experimental Therapeutics Program on the identification, design and development of novel compounds targeting the identified cryptic pocket and other allosteric sites. We expect some of these successes to lead to drugs that can potentially be used in precision and personalized therapies to treat RET-related cancers in the future, Plaza-Menacho said. Refractory mutations conferring resistance to these inhibitors have already been described. The study authors also provide guidelines for the design of new drugs capable of overcoming the effects of such refractory mutations.
Reference: Shehata MA, Contreras J, Martín-Hurtado A, et al. Structural and dynamic determinants of highly selective RET kinase inhibition reveal cryptic pharmacogability. J. Adv. Res. 2022. do: 10.1016/j.jare.2022.05.004
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