Identification of Dihydroorotate Dehydrogenase Inhibitors Using the Cell Painting Assay.
Identification of Dihydroorotate Dehydrogenase Inhibitors Using the Cell Painting Assay.
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DOI：
10.1002/cbic.202200475
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发表时间：
2022-11-18
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影响因子：
--
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分析方法已越来越多地用于疾病相关表型或复合扰动的表征，因为它们提供了对受损细胞状态的广泛，公正的看法。我们报告了使用细胞绘画分析（CPA）的形态学分析可以检测新的嘧啶生物合成的调节剂，特别是二氢羟酸脱氢酶（DHODH）。CPA可以区分嘧啶和叶酸代谢的损害，两者都影响细胞核苷酸池。所鉴定的形态特征与DHODH抑制剂和线粒体呼吸链功能紧密偶联的复合体III以及DHODH下游的UMP合酶共享。CPA似乎特别适合于检测DHODH抑制剂在细胞中的作用位点。由于DHODH是一个经过验证的治疗靶点，CPA将能够公正地鉴定DHODH抑制剂和新生嘧啶生物合成抑制剂，用于生物学研究和药物发现。已经鉴定出一种形态指纹，用于抑制新的嘧啶生物合成，这是由参与嘧啶合成的酶抑制剂如DHODH和复合物III抑制剂共享的。这种生物活性簇可以用来识别这些目标的进一步调节剂。
Profiling approaches have been increasingly employed for the characterization of disease‐relevant phenotypes or compound perturbation as they provide a broad, unbiased view on impaired cellular states. We report that morphological profiling using the cell painting assay (CPA) can detect modulators of de novo pyrimidine biosynthesis and of dihydroorotate dehydrogenase (DHODH) in particular. The CPA can differentiate between impairment of pyrimidine and folate metabolism, which both affect cellular nucleotide pools. The identified morphological signature is shared by inhibitors of DHODH and the functionally tightly coupled complex III of the mitochondrial respiratory chain as well as by UMP synthase, which is downstream of DHODH. The CPA appears to be particularly suited for the detection of DHODH inhibitors at the site of their action in cells. As DHODH is a validated therapeutic target, the CPA will enable unbiased identification of DHODH inhibitors and inhibitors of de novo pyrimidine biosynthesis for biological research and drug discovery. A morphological fingerprint has been identified for the suppression of de novo pyrimidine biosynthesis which is shared by inhibitors of enzymes that are involved in pyrimidine synthesis such as DHODH and inhibitors of complex III. This bioactivity cluster can be employed to identify further modulators of these targets.
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DOI：
10.1002/anie.202016575
发表时间：
2021-07-12
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Karageorgis G;Foley DJ;Laraia L;Brakmann S;Waldmann H
通讯作者：
Waldmann H
影响因子：
16.6
作者：
Ladds MJGW;van Leeuwen IMM;Drummond CJ;Chu S;Healy AR;Popova G;Pastor Fernández A;Mollick T;Darekar S;Sedimbi SK;Nekulova M;Sachweh MCC;Campbell J;Higgins M;Tuck C;Popa M;Safont MM;Gelebart P;Fandalyuk Z;Thompson AM;Svensson R;Gustavsson AL;Johansson L;Färnegårdh K;Yngve U;Saleh A;Haraldsson M;D'Hollander ACA;Franco M;Zhao Y;Håkansson M;Walse B;Larsson K;Peat EM;Pelechano V;Lunec J;Vojtesek B;Carmena M;Earnshaw WC;McCarthy AR;Westwood NJ;Arsenian-Henriksson M;Lane DP;Bhatia R;McCormack E;Laín S
通讯作者：
Laín S
影响因子：
3.5
作者：
BECKER, WF;VONJAGOW, G;STEGLICH, W
通讯作者：
STEGLICH, W
影响因子：
16.6
作者：
Grigalunas M;Burhop A;Zinken S;Pahl A;Gally JM;Wild N;Mantel Y;Sievers S;Foley DJ;Scheel R;Strohmann C;Antonchick AP;Waldmann H
通讯作者：
Waldmann H
影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM