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具有泛癌治疗功效的小分子蛋白质组装调节剂。

Small molecule protein assembly modulators with pan-cancer therapeutic efficacy.

作者信息

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

机构信息

Prosetta Biosciences, San Francisco, CA, USA.

University of California San Francisco, San Francisco, CA, USA.

出版信息

Open Biol. 2024 Dec;14(12):240210. doi: 10.1098/rsob.240210. Epub 2024 Dec 18.

DOI:10.1098/rsob.240210
PMID:39689856
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11651915/
Abstract

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.

摘要

研究了两种结构不相关的小分子化学类型，分别以化合物PAV - 617和PAV - 951为代表，它们在细胞培养中分别对猴痘病毒（原称猴痘病毒）和人类免疫缺陷病毒（HIV）具有抗病毒活性，以评估其抗癌疗效。每种化合物都表现出明显的泛癌细胞毒性且具有合理的药代动力学。在非癌细胞系和小鼠中，在达到活性浓度药物暴露的剂量下均未显示出毒性。两种化学类型的抗肿瘤特性在针对A549人肺癌的小鼠异种移植模型中得到验证，其中一种化学类型还在针对HT - 29结直肠癌的模型中得到验证。这些化合物的靶点是非传统的：每种化合物都与不同的瞬时、能量依赖性多蛋白复合物结合。用这些化合物进行治疗会改变靶点多蛋白复合物，其方式似乎是消除了对癌症生存和进展至关重要的一个障碍，该障碍存在于不受控制的增殖和凋亡之间的稳态联系中。这些化合物为开发新型、下一代、无毒的泛癌治疗药物提供了起点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0515/11651915/dc3d9dcf241f/rsob.240210.f007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0515/11651915/70c7cdca1a09/rsob.240210.f001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0515/11651915/08e6977c9029/rsob.240210.f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0515/11651915/26e28b30639c/rsob.240210.f004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0515/11651915/534d1091db34/rsob.240210.f005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0515/11651915/d77c8f21f336/rsob.240210.f006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0515/11651915/dc3d9dcf241f/rsob.240210.f007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0515/11651915/70c7cdca1a09/rsob.240210.f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0515/11651915/c793e62236eb/rsob.240210.f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0515/11651915/08e6977c9029/rsob.240210.f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0515/11651915/26e28b30639c/rsob.240210.f004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0515/11651915/534d1091db34/rsob.240210.f005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0515/11651915/d77c8f21f336/rsob.240210.f006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0515/11651915/dc3d9dcf241f/rsob.240210.f007.jpg

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