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化学探针双酰胺（CCT251236）的发现：一种通过热休克转录因子1（HSF1）表型筛选得到的口服生物可利用的有效嘧啶配体。

Discovery of a Chemical Probe Bisamide (CCT251236): An Orally Bioavailable Efficacious Pirin Ligand from a Heat Shock Transcription Factor 1 (HSF1) Phenotypic Screen.

作者信息

Cheeseman Matthew D, Chessum Nicola E A, Rye Carl S, Pasqua A Elisa, Tucker Michael J, Wilding Birgit, Evans Lindsay E, Lepri Susan, Richards Meirion, Sharp Swee Y, Ali Salyha, Rowlands Martin, O'Fee Lisa, Miah Asadh, Hayes Angela, Henley Alan T, Powers Marissa, Te Poele Robert, De Billy Emmanuel, Pellegrino Loredana, Raynaud Florence, Burke Rosemary, van Montfort Rob L M, Eccles Suzanne A, Workman Paul, Jones Keith

机构信息

Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.

Division of Structural Biology at The Institute of Cancer Research , London SW7 3RP, United Kingdom.

出版信息

J Med Chem. 2017 Jan 12;60(1):180-201. doi: 10.1021/acs.jmedchem.6b01055. Epub 2016 Dec 22.

DOI:10.1021/acs.jmedchem.6b01055
PMID:28004573
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6014687/
Abstract

Phenotypic screens, which focus on measuring and quantifying discrete cellular changes rather than affinity for individual recombinant proteins, have recently attracted renewed interest as an efficient strategy for drug discovery. In this article, we describe the discovery of a new chemical probe, bisamide (CCT251236), identified using an unbiased phenotypic screen to detect inhibitors of the HSF1 stress pathway. The chemical probe is orally bioavailable and displays efficacy in a human ovarian carcinoma xenograft model. By developing cell-based SAR and using chemical proteomics, we identified pirin as a high affinity molecular target, which was confirmed by SPR and crystallography.

摘要

表型筛选聚焦于测量和量化离散的细胞变化，而非对单个重组蛋白的亲和力，作为一种高效的药物发现策略，最近重新引起了人们的关注。在本文中，我们描述了一种新化学探针双酰胺（CCT251236）的发现，该探针是通过无偏向性表型筛选鉴定出的，用于检测热休克因子1（HSF1）应激途径的抑制剂。该化学探针具有口服生物利用度，并在人卵巢癌异种移植模型中显示出疗效。通过开展基于细胞的构效关系研究并运用化学蛋白质组学，我们确定了 pirin 为高亲和力分子靶点，这一结果通过表面等离子体共振（SPR）和晶体学得到了证实。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6126/6014687/fcecf19208fa/jm-2016-01055c_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6126/6014687/411f15c51411/jm-2016-01055c_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6126/6014687/9ba218cf7aac/jm-2016-01055c_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6126/6014687/322b6a99e3b5/jm-2016-01055c_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6126/6014687/7dcdb5a37b23/jm-2016-01055c_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6126/6014687/651a7576f761/jm-2016-01055c_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6126/6014687/bdb981b651ae/jm-2016-01055c_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6126/6014687/080632d3671c/jm-2016-01055c_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6126/6014687/3c932f23a4c9/jm-2016-01055c_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6126/6014687/fcecf19208fa/jm-2016-01055c_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6126/6014687/411f15c51411/jm-2016-01055c_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6126/6014687/9ba218cf7aac/jm-2016-01055c_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6126/6014687/322b6a99e3b5/jm-2016-01055c_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6126/6014687/7dcdb5a37b23/jm-2016-01055c_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6126/6014687/651a7576f761/jm-2016-01055c_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6126/6014687/bdb981b651ae/jm-2016-01055c_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6126/6014687/080632d3671c/jm-2016-01055c_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6126/6014687/3c932f23a4c9/jm-2016-01055c_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6126/6014687/fcecf19208fa/jm-2016-01055c_0007.jpg

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