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靶向强效且选择性结合物和降解剂的暗脂质激酶 PIP4K2C。

Targeting the Dark Lipid Kinase PIP4K2C with a Potent and Selective Binder and Degrader.

机构信息

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.

Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.

出版信息

Angew Chem Int Ed Engl. 2023 Apr 24;62(18):e202302364. doi: 10.1002/anie.202302364. Epub 2023 Mar 27.

DOI:10.1002/anie.202302364
PMID:36898968
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10150580/
Abstract

Phosphatidylinositol 5-phosphate 4-kinase, type II, gamma (PIP4K2C) remains a poorly understood lipid kinase with minimal enzymatic activity but potential scaffolding roles in immune modulation and autophagy-dependent catabolism. Achieving potent and selective agents for PIP4K2C while sparing other lipid and non-lipid kinases has been challenging. Here, we report the discovery of the highly potent PIP4K2C binder TMX-4102, which shows exclusive binding selectivity for PIP4K2C. Furthermore, we elaborated the PIP4K2C binder into TMX-4153, a bivalent degrader capable of rapidly and selectively degrading endogenous PIP4K2C. Collectively, our work demonstrates that PIP4K2C is a tractable and degradable target, and that TMX-4102 and TMX-4153 are useful leads to further interrogate the biological roles and therapeutic potential of PIP4K2C.

摘要

磷脂酰肌醇 5-磷酸 4-激酶，II 型，γ（PIP4K2C）仍然是一种了解甚少的脂质激酶，其酶活性极小，但在免疫调节和自噬依赖性分解代谢中具有潜在的支架作用。实现对 PIP4K2C 的有效和选择性药物而不损害其他脂质和非脂质激酶一直具有挑战性。在这里，我们报告了高度有效的 PIP4K2C 结合物 TMX-4102 的发现，该结合物对 PIP4K2C 表现出独特的结合选择性。此外，我们将 PIP4K2C 结合物进一步细化为 TMX-4153，这是一种双价降解剂，能够快速和选择性地降解内源性 PIP4K2C。总的来说，我们的工作表明 PIP4K2C 是一个可及和可降解的靶标，TMX-4102 和 TMX-4153 是进一步研究 PIP4K2C 的生物学作用和治疗潜力的有用先导物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4483/10150580/c9ad5897264a/nihms-1886131-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4483/10150580/aaa2fffbf258/nihms-1886131-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4483/10150580/050f0ab2b008/nihms-1886131-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4483/10150580/c11193185a88/nihms-1886131-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4483/10150580/871ce976e2ac/nihms-1886131-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4483/10150580/c5deedc38288/nihms-1886131-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4483/10150580/c9ad5897264a/nihms-1886131-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4483/10150580/aaa2fffbf258/nihms-1886131-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4483/10150580/050f0ab2b008/nihms-1886131-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4483/10150580/c11193185a88/nihms-1886131-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4483/10150580/871ce976e2ac/nihms-1886131-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4483/10150580/c5deedc38288/nihms-1886131-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4483/10150580/c9ad5897264a/nihms-1886131-f0007.jpg

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J Med Chem. 2023 Jan 12;66(1):804-821. doi: 10.1021/acs.jmedchem.2c01693. Epub 2022 Dec 14.
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Discovery of small molecule ligands for the von Hippel-Lindau (VHL) E3 ligase and their use as inhibitors and PROTAC degraders.
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