Abstract
Despite intensive efforts in the search for small molecules with anti-cancer activity, it remains challenging to achieve both high effectiveness and safety, since many agents lack the selectivity to only act on cancer cells. The interface of two apoptotic proteins, myeloid cell leukemia-1 (Mcl-1) and p53 upregulated modulator of apoptosis (PUMA), has been recently affirmed as a target for treating cancers, as the disruption of Mcl-1-PUMA binding can reduce cancer cell survival and protect normal cells from apoptosis. However, therapeutic agents that target this interface are yet to be found. In this work, we combined pharmacophore modelling and biological tests to seek small molecules which target the Mcl-1-PUMA interface. For the first time, a small-molecule compound was identified. Its dual activity has been validated to reduce PUMA-dependent apoptosis while deactivating Mcl-1-mediated anti-apoptosis in cancer cells. Our results would provide a new avenue for the development of effective and safe anti-cancer agents.
Highlights
Apoptosis is a critical cellular process in maintaining normal tissue homeostasis [1]
The starting point for our study is the determination of compounds that potentially act on the myeloid cell leukemia-1 (Mcl-1)-p53 upregulated modulator of apoptosis (PUMA) interface, using pharmacophore-based virtual screening
Molecular dynamics (MD) simulations of a 50 ns timescale were performed with the Mcl-1-PUMA complex models to provide the energetics and plasticity details of the interface
Summary
Apoptosis is a critical cellular process in maintaining normal tissue homeostasis [1]. Its dual activity has been validated to reduce PUMA-dependent apoptosis while deactivating Mcl-1-mediated anti-apoptosis in cancer cells.
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