The novel diarylurea derivative HPT-15 for potential treatment of triple-negative breast cancer via dual inhibition of the mTOR and MAPK pathways

Abstract

Dysregulation of the mTOR serine/threonine protein kinase has been linked to the pathogenesis and prognosis of triple-negative breast cancer (TNBC). Meanwhile, the MAPK signaling pathway has been implicated in the progression and drug resistance of TNBC. Therefore, dual inhibition of the mTOR and MAPK pathways presents a promising therapeutic strategy against TNBC. Here, we report the design and synthesis of a novel selective mTOR inhibitor, HPT-15. Molecular docking and dynamics simulations confirmed that HPT-15 exhibited superior binding stability with mTOR as compared to the dual-target inhibitor PKI-587. In vitro experiments demonstrated that HPT-15 significantly inhibited the proliferation, migration, and invasion of TNBC cells. The anti-tumor effects of HPT-15 were mediated by inhibited phosphorylation of the downstream mTOR proteins 4EBP1 and Akt. RNA sequencing revealed that HPT-15 induced cell death by modulating the MAPK signaling pathway, cell cycle progression, and autophagy. In vivo experiments further confirmed that HPT-15 effectively suppressed tumor growth without apparent toxic side effects. These findings promote the potential of HPT-15 for treatment of TNBC.

Keywords: Mitogen-activated protein kinase; RNA sequencing; Selective mTOR inhibitor HPT-15; Triple-negative breast cancer.