Small molecule protein assembly modulators with pan-cancer therapeutic efficacy

• Published in: Open biology 2024-12, Vol.14 (12), p.240210
• Main Authors: Lingappa, Anuradha F, Akintunde, Olayemi, Samueli, Erin, Ewald, Connie, Michon, Maya, Ziari, Niloufar, Lu, Ming, Yu, Shao Feng, Froehlich, Markus, Le, Phuong Uyen, Fernandez, Yuniel, Mallesh, Suguna, Lin, Jim, Kitaygorodskyy, Anatoliy, Solas, Dennis, Reed, Jonathan C, Lingappa, Jaisri R, Müller-Schiffmann, Andreas, Korth, Carsten, Prasad, Dharma, Nalca, Aysegul, Aston, Emily, Fabbri, Brad, Anand, Sanjeev K, Campi, Thomas W, Petrouski, Emma, Dey, Debendranath, Andrews, David W, Rubenstein, James L, Lingappa, Vishwanath R
• Format: Article
• Language: English
• Subjects: A549 Cells; allosteric modulator; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; drug discovery; HIV - drug effects; HT29 Cells; Humans; Mice; Monkeypox virus - drug effects; multi-protein complex; Neoplasms - drug therapy; Neoplasms - metabolism; pan-cancer therapeutics; restoration of homeostasis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Small Molecule Libraries - therapeutic use; Xenograft Model Antitumor Assays
• ISSN: 2046-2441; 2046-2441
• DOI: 10.1098/rsob.240210

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.