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用于再生医学的LATS1和LATS2激酶抑制剂的发现与优化

Discovery and Optimization of LATS1 and LATS2 Kinase Inhibitors for Use in Regenerative Medicine.

作者信息

Morris Patrick J, Duveau Damien Y, Ceribelli Michele, Tosto Frances Anne, Love Dara N, Scherer Bridget S, Tao Dingyin, Fang Yuhong, Evsen Lale, Kotler Samuel A, LeClair Christopher A, Rai Ganesha, Thomas Craig J, Hoyt Scott B

机构信息

Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, United States.

出版信息

J Med Chem. 2025 Aug 28;68(16):17499-17515. doi: 10.1021/acs.jmedchem.5c01027. Epub 2025 Aug 6.

DOI:10.1021/acs.jmedchem.5c01027
PMID:40768682
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12406206/
Abstract

The Large Tumor Suppressor Kinases 1 and 2 (LATS1/2) are serine/threonine kinases that play an essential role in Hippo pathway activation and influence multiple physiological events ranging from organ growth to tissue regeneration. As a result, pharmacological inhibition of LATS1/2 represents a promising strategy for therapeutic intervention in multiple indications. Within, we present the discovery of potent and selective inhibitors of the kinases LATS1 and LATS2. Using a scaffold hopping strategy from the reported AKT inhibitor AT-7867 (1) we pursued a series of structure activity relationship (SAR) studies that dramatically improved potency versus LATS1 and LATS2, while concurrently improving kinome-wide selectivity. ADME properties were further optimized via introduction of conformational restriction into the target molecule, to lead to compound 27 which possesses potent inhibitory activity against both LATS1 and LATS2 and proof of concept activity in wound healing models.

摘要

大肿瘤抑制激酶1和2（LATS1/2）是丝氨酸/苏氨酸激酶，在河马通路激活中起关键作用，并影响从器官生长到组织再生等多种生理过程。因此，对LATS1/2进行药理抑制是多种适应症治疗干预的一种有前景的策略。在此，我们展示了LATS1和LATS2激酶强效和选择性抑制剂的发现。利用已报道的AKT抑制剂AT-7867（1）的骨架跳跃策略，我们进行了一系列构效关系（SAR）研究，显著提高了对LATS1和LATS2的效力，同时提高了对整个激酶组的选择性。通过在目标分子中引入构象限制进一步优化了ADME性质，得到了化合物27，其对LATS1和LATS2均具有强效抑制活性，并在伤口愈合模型中具有概念验证活性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d3/12406206/81eccf8e9ab6/jm5c01027_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d3/12406206/1fcb20de7d64/jm5c01027_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d3/12406206/45ec17a42f03/jm5c01027_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d3/12406206/25202ba833df/jm5c01027_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d3/12406206/fdde4668cb08/jm5c01027_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d3/12406206/53f000d96f9d/jm5c01027_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d3/12406206/f54ff675c12d/jm5c01027_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d3/12406206/81eccf8e9ab6/jm5c01027_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d3/12406206/1fcb20de7d64/jm5c01027_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d3/12406206/45ec17a42f03/jm5c01027_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d3/12406206/25202ba833df/jm5c01027_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d3/12406206/fdde4668cb08/jm5c01027_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d3/12406206/53f000d96f9d/jm5c01027_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d3/12406206/f54ff675c12d/jm5c01027_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d3/12406206/81eccf8e9ab6/jm5c01027_0007.jpg

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本文引用的文献

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NIBR-LTSi is a selective LATS kinase inhibitor activating YAP signaling and expanding tissue stem cells in vitro and in vivo.NIBR-LTSi 是一种选择性的 LATS 激酶抑制剂，可激活 YAP 信号通路，并在体外和体内扩增组织干细胞。
Cell Stem Cell. 2024 Apr 4;31(4):554-569.e17. doi: 10.1016/j.stem.2024.03.003.
2
Inhibition of LATS kinases reduces tumorigenicity and increases the sensitivity of human chronic myelogenous leukemia cells to imatinib.抑制 LATS 激酶可降低肿瘤生成能力，并增加人慢性髓性白血病细胞对伊马替尼的敏感性。
Sci Rep. 2024 Feb 18;14(1):3993. doi: 10.1038/s41598-024-54728-z.
3
Diabetic Foot Ulcers: A Review.
糖尿病足溃疡：综述。
JAMA. 2023 Jul 3;330(1):62-75. doi: 10.1001/jama.2023.10578.
4
The Hippo signalling pathway and its implications in human health and diseases.Hippo 信号通路及其在人类健康和疾病中的意义。
Signal Transduct Target Ther. 2022 Nov 8;7(1):376. doi: 10.1038/s41392-022-01191-9.
5
Therapeutic Strategies to Reduce Burn Wound Conversion.减少烧伤创面转化的治疗策略。
Medicina (Kaunas). 2022 Jul 11;58(7):922. doi: 10.3390/medicina58070922.
6
Development of an improved inhibitor of Lats kinases to promote regeneration of mammalian organs.开发改良的 Lats 激酶抑制剂以促进哺乳动物器官的再生。
Proc Natl Acad Sci U S A. 2022 Jul 12;119(28):e2206113119. doi: 10.1073/pnas.2206113119. Epub 2022 Jul 8.
7
Small molecule LATS kinase inhibitors block the Hippo signaling pathway and promote cell growth under 3D culture conditions.小分子 LATS 激酶抑制剂在 3D 培养条件下阻断 Hippo 信号通路并促进细胞生长。
J Biol Chem. 2022 Apr;298(4):101779. doi: 10.1016/j.jbc.2022.101779. Epub 2022 Feb 26.
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Transcriptional repression of estrogen receptor alpha by YAP reveals the Hippo pathway as therapeutic target for ER breast cancer.YAP 通过转录抑制雌激素受体 α，揭示 Hippo 通路是 ER 阳性乳腺癌的治疗靶点。
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9
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