Analogs of MKT-077, a rhodocyanine dye analog that inhibits mortalin, effectively and consistently decreased propagation of 2 medullary thyroid carcinoma (MTC) cells in live cultures, as published in the International Journal of Molecular Sciences.

A team of researchers led by Hong studied 3 MKT-077 analogs with positive results, out of which 2 of them, JG-98 and JG-194, inhibited propagation and reduced viability in TT and MZ-CRC-1 cells that were resistant to vandetanib and cabozantinib. Another analog, JG-231, suppressed MTC cells in mice xenografts and further improved microsomal stability.

Knowing that the physiopathology of MTC commonly involves mutations in the RET proto-oncogene, suppressing mortalin, a mitochondrial chaperone of the heat shock proteins 70 (HSP70) family that consequently downregulates RET, may propose a therapeutic target. This has been further confirmed since mortalin was found to be essential for mitochondrial bioenergetics in MTC cells.


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Previous assays with MKT-077 also reported high toxicity in animals. In this study, the analogs used provided substantial benefits compared to MKT-077, such as selective HSP70 inhibition and higher bioavailability. “In typical medicinal chemistry campaigns, the goal is to identify a single compound that is the most potent and metabolically stable. Such a ‘lead’ compound is then deployed in other disease models,” the authors said.

“However, because of differences in mitochondrial potential, expression of drug efflux proteins and other factors, it seems possible (or even likely) that the absolute rank-ordering of compounds in a series might be different in different cell lines. In our case, the MKT-077 analogs were designed for potency in breast and prostate cancer cell lines.”

When comparing the effects of JG-194 in MTC cells vs already known and used RET-inhibiting drugs such as vandetanib and cabozantinib at equivalent doses, the results were similar; nonetheless, JG-194 was also effective in progenies resistant to the currently available drugs, highlighting the therapeutic role of mortalin inhibitors. Further studies have yet to be done to overcome current limitations; for example, JG-231 showcased lower effectiveness in vivo when compared to JG-194 in vitro, but JG-194 has poor metabolic stability.

“In conclusion, our current data demonstrate an advance in mortalin targeting in MTC cells and, consistent with our previous observations, support the potential of mortalin as a target for the design of a molecular therapy for MTC,” the authors wrote.

Reference

Hong S, Starenki D, Johnson O, Gestwicki J, Park J. Analogs of the heat shock protein 70 inhibitor MKT-077 suppress medullary thyroid carcinoma cells. Int J Mol Sci. Published online January 19, 2022. doi:10.3390/ijms23031063