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Analogs of the Heat Shock Protein 70 Inhibitor MKT-077 Suppress Medullary Thyroid Carcinoma Cells
Seung-Keun Hong1, Dmytro Starenki1, Oleta T Johnson2
1Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Abstract:
Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor mainly caused by mutations in the RET proto-oncogene. We previously demonstrated that depletion of the mitochondrial molecular chaperone, mortalin, can effectively suppress human MTC cells in culture and in mouse xenografts, by disrupting mitochondrial bioenergetics and subsequently inducing apoptosis and RET downregulation. Similar effects were induced by MKT-077, a water-soluble rhodocyanine dye analog known to inhibit mortalin, but with notable toxicity in animals. These observations led us to evaluate recently developed MKT-077 analogs that exhibited higher selectivity to HSP70 proteins and improved bioavailability. We validated the MTC cell-suppressive effects of mortalin depletion in three-dimensional cultures of the human MTC lines, TT, and MZ-CRC-1, and then evaluated different MKT-077 analogs in two- and three-dimensional cell cultures, to show that the MKT-077 analogs, JG-98 and JG-194, effectively and consistently inhibited propagation of TT and MZ-CRC-1 cells in these cultures. Of note, these compounds also effectively suppressed the viability of TT and MZ-CRC-1 progenies resistant to vandetanib and cabozantinib. Moreover, JG-231, an analog with improved microsomal stability, consistently suppressed TT and MZ-CRC-1 xenografts in mice. These data suggest that mortalin inhibition may have therapeutic potential for MTC.
Insights
New MKT-077 analogs, JG-98, JG-194, and JG-231, effectively suppress medullary thyroid carcinoma (MTC) cell growth and xenografts. These compounds target mortalin, offering potential new therapies for MTC, even in drug-resistant cases.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor often driven by RET proto-oncogene mutations.
- Mortalin, a mitochondrial chaperone, depletion suppresses MTC by disrupting bioenergetics, inducing apoptosis, and downregulating RET.
- MKT-077 inhibits mortalin but shows animal toxicity; newer analogs offer improved selectivity and bioavailability.
Purpose of the Study:
- To evaluate novel MKT-077 analogs for their efficacy in suppressing MTC cell proliferation and tumor growth.
- To assess the therapeutic potential of mortalin inhibition in MTC, including drug-resistant models.
Main Methods:
- Validation of mortalin depletion effects in 2D and 3D MTC cell cultures (TT, MZ-CRC-1).
- Screening of MKT-077 analogs (JG-98, JG-194, JG-231) for MTC cell growth inhibition.
- Evaluation of analog efficacy in MTC cells resistant to vandetanib and cabozantinib.
- Assessment of JG-231 in mouse xenograft models of MTC.
Main Results:
- MKT-077 analogs JG-98 and JG-194 effectively inhibited TT and MZ-CRC-1 MTC cell propagation in 2D and 3D cultures.
- These analogs suppressed MTC cells resistant to vandetanib and cabozantinib.
- JG-231 demonstrated consistent suppression of MTC xenografts in mice, showing improved microsomal stability.
Conclusions:
- Mortalin inhibition by novel MKT-077 analogs represents a promising therapeutic strategy for MTC.
- These analogs show potential for treating MTC, including cases resistant to current therapies.
- Further development of mortalin inhibitors warrants investigation for MTC treatment.
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