Perhexiline (maleate)

Perhexiline is a carnitine palmitoyltransferase 1 (CPT1) and CPT2 inhibitor that was originally developed as an anti-anginal drug in the 1970s.^1,2,3 It inhibits rat heart and liver CPT1 (IC₅₀ = 77 and 148 µM, respectively) and rat heart CPT2 (IC₅₀ = 79 µM).^1,2 Inhibition of CPT reduces uptake of long-chain fatty acids into the mitochondria, thereby shifting cellular metabolism from β-oxidation to glycolysis. Perhexilin inhibits mTORC1 signaling at 10 µM and induces autophagy ~7-fold at a concentration of 10 µM in MCF-7 cells.⁴

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1. Kennedy, J.A., Unger, S.A., and Horowitz, J.D. Inhibition of carnitine palmitoyltransferase-1 in rat heart and liver by perhexiline and amiodarone. Biochem. Pharmacol. 52(2), 273-280 (1996).

2. Kennedy, J.A., Kiosoglous, A.J., Murphy, G.A., et al. Effect of perhexiline and oxfenicine on myocardial function and metabolism during low-flow ischemia/reperfusion in the isolated rat heart. J. Cardiovasc. Pharmacol. 36(6), 794-801 (2000).

3. Ashrafian, H., Horowitz, J.D., and Frenneaux, M.P. Perhexiline. Cardiovasc. Drug Rev. 25(1), 76-97 (2007).

4. Balgi, A.D., Fonseca, B.D., Donohue, E., et al. Screen for chemical modulators of autophagy reveals novel therapeutic inhibitors of mTORC1 signaling. PLoS One 4(9), e7124 (2009).

Xu, S., Catapang, A., Braas, D., et al. A precision therapeutic strategy for hexokinase 1-null, hexokinase 2-positive cancers. Cancer & Metab. 6:7, (2018).