Small Molecule Assembly Modulators with Pan-Cancer Therapeutic Efficacy

Lingappa, A. F.; Akintunde, O.; Ewald, C.; Froehlich, M.; Ziari, N.; Yu, S. F.; Michon, M.; Mallesh, S.; Lin, J.; Kitaygorodskyy, A.; Solas, D.; Reed, J. C.; Lingappa, J. R.; Mueller-Schiffmann, A.; Korth, C.; Prasad, M. D.; Ashton, E.; Fabbri, B.; Nalca, A.; Petrouski, E.; Dey, D.; Andrews, D. W.; Lingappa, V. R.

doi:10.1101/2022.09.28.509937

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bioRxiv · 10.1101/2022.09.28.509937

Small Molecule Assembly Modulators with Pan-Cancer Therapeutic Efficacy

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Abstract

Two structurally-unrelated small molecule chemotypes, represented by compounds PAV-617 and PAV-951 with antiviral activity in cell culture against monkeypox virus (MPXV) and human immunodeficiency virus (HIV) respectively, were studied for anti-cancer efficacy. Each exhibited apparent pan-cancer cytotoxicity, reasonable pharmacokinetics, and non-toxicity in mice at active concentrations. Anti-tumor 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 containing the protein TRIM28/KAP1, an allosteric modulator known to regulate mechanisms underlying viral and nonviral disease states including cancer. Treatment with these compounds alters the target multi-protein complexes in a manner consistent with allosteric modulation as their mechanism of action. These compounds appear to remove a block, crucial for cancer survival and progression, on the homeostatic linkage of uncontrolled cellular proliferation to apoptosis. These compounds provide starting points for development of next-generation non-toxic, pan-cancer therapeutics.

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Lingappa, A. F., Akintunde, O., Ewald, C., Froehlich, M., Ziari, N., Yu, S. F., Michon, M., Mallesh, S., Lin, J., Kitaygorodskyy, A., Solas, D., Reed, J. C., Lingappa, J. R., Mueller-Schiffmann, A., Korth, C., Prasad, M. D., Ashton, E., Fabbri, B., Nalca, A., Petrouski, E., Dey, D., Andrews, D. W., Lingappa, V. R.. 2022-09-30. Small Molecule Assembly Modulators with Pan-Cancer Therapeutic Efficacy. https://doi.org/10.1101/2022.09.28.509937

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