Small molecule protein assembly modulators with pan-cancer therapeutic efficacy

Small molecule protein assembly modulators with pan-cancer therapeutic efficacy

Two structurally unrelated small molecule chemotypes, represented by compounds PAV-617 and PAV-951, with antiviral activity in cell culture against Mpox virus (formerly known as monkeypox virus) and human immunodeficiency virus (HIV) respectively, were studied for anti-cancer efficacy. Each exhibite...

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Main Authors: Anuradha F. Lingappa, Olayemi Akintunde, Erin Samueli, Connie Ewald, Maya Michon, Niloufar Ziari, Ming Lu, Shao Feng Yu, Markus Froehlich, Phuong Uyen Le, Yuniel Fernandez, Suguna Mallesh, Jim Lin, Anatoliy Kitaygorodskyy, Dennis Solas, Jonathan C. Reed, Jaisri R. Lingappa, Andreas Müller-Schiffmann, Carsten Korth, Dharma Prasad, Aysegul Nalca, Emily Aston, Brad Fabbri, Sanjeev K. Anand, Thomas W. Campi, Emma Petrouski, Debendranath Dey, David W. Andrews, James L. Rubenstein, Vishwanath R. Lingappa
Format: Article
Language:English
Published: The Royal Society 2024-12-01
Series:Open Biology
Subjects:
drug discovery
pan-cancer therapeutics
allosteric modulator
restoration of homeostasis
multi-protein complex
Online Access:https://royalsocietypublishing.org/doi/10.1098/rsob.240210
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Summary:Two structurally unrelated small molecule chemotypes, represented by compounds PAV-617 and PAV-951, with antiviral activity in cell culture against Mpox virus (formerly known as monkeypox virus) and human immunodeficiency virus (HIV) respectively, were studied for anti-cancer efficacy. Each exhibited apparent pan-cancer cytotoxicity with reasonable pharmacokinetics. Non-toxicity is demonstrated in a non-cancer cell line and in mice at doses achieving drug exposure at active concentrations. Anti-tumour properties of both chemotypes were validated in mouse xenografts against A549 human lung cancer and, for one of the chemotypes, against HT-29 colorectal cancer. The targets of these compounds are unconventional: each binds to a different transient, energy-dependent multi-protein complex. Treatment with these compounds alters the target multi-protein complexes in a manner that appears to remove a block, crucial for cancer survival and progression, on a homeostatic linkage between uncontrolled proliferation and apoptosis. These compounds provide starting points for development of novel, next-generation, non-toxic, pan-cancer therapeutics.
ISSN:2046-2441

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