TRPM8 has recently emerged as a druggable target in prostate cancer (PC) and TRPM8 modulators have been proposed as potential anticancer agents in this pathology. We have recently demonstrated their effectiveness in a castration-resistant prostate cancer (CRPC) model that is usually resistant to androgen deprivation therapy (ADT) and is considered the most aggressive form of PC. This is why the discovery of selective, effective, and potent TRPM8 modulators would improve the molecular arsenal in support of PC standard-of-care treatments. In the present paper we describe the design and the synthesis of a new series of TRPM8 antagonists, preliminarily characterized in vitro for their potency and selectivity by fluorimetric calcium assays. The preliminary screening allowed the identification of several potent (0.11 μM < IC50 < 0.49 μM) and selective compounds. The most potent derivatives were further characterized by patch-clamp electrophysiology assays, confirming their noteworthy activity. Moreover, the behavior of these compounds was investigated in 2D and 3D models of PC. These TRPM8 antagonists showed remarkable efficacy in inhibiting the growth induced by androgen in various PC cells as well as in CRPC models, confirming their potential as anticancer agents.

New TRPM8 blockers exert anticancer activity over castration-resistant prostate cancer models.

Pia Giovannelli;Marzia Di Donato;Gabriella Castoria;Antimo Migliaccio;
2022

Abstract

TRPM8 has recently emerged as a druggable target in prostate cancer (PC) and TRPM8 modulators have been proposed as potential anticancer agents in this pathology. We have recently demonstrated their effectiveness in a castration-resistant prostate cancer (CRPC) model that is usually resistant to androgen deprivation therapy (ADT) and is considered the most aggressive form of PC. This is why the discovery of selective, effective, and potent TRPM8 modulators would improve the molecular arsenal in support of PC standard-of-care treatments. In the present paper we describe the design and the synthesis of a new series of TRPM8 antagonists, preliminarily characterized in vitro for their potency and selectivity by fluorimetric calcium assays. The preliminary screening allowed the identification of several potent (0.11 μM < IC50 < 0.49 μM) and selective compounds. The most potent derivatives were further characterized by patch-clamp electrophysiology assays, confirming their noteworthy activity. Moreover, the behavior of these compounds was investigated in 2D and 3D models of PC. These TRPM8 antagonists showed remarkable efficacy in inhibiting the growth induced by androgen in various PC cells as well as in CRPC models, confirming their potential as anticancer agents.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11591/471247
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