Discovery of potent and selective PROTACs for the protein kinase LZK for the treatment of head and neck cancer.

IF 4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Meghri Katerji, Knickole L Bergman, Eric Lindberg, Maxine R Rubin, Amy L Funk, Carolyn C Woodroofe, Katherine Nyswaner, Kamila Karpińska, Remigiusz Serwa, Anna Marusiak, Rolf E Swenson, John F Brognard
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引用次数: 0

Abstract

Leucine zipper-bearing kinase (LZK) is overexpressed in 20% of head and neck squamous cell carcinoma (HNSCC) cases and has emerged as a promising therapeutic target in this cancer subtype. LZK promotes HNSCC survival and proliferation by stabilizing c-MYC and GOF-p53 in kinase-dependent and -independent manners, respectively. Herein, we developed a new series of LZK degraders utilizing proteolysis-targeting chimera (PROTAC) technology by modulating the linker region or LZK warhead of LZK-targeting PROTAC-21A, previously developed by our lab. Among the 27 PROTACs synthesized and tested, PROTAC 17 was found to be the most potent, degrading LZK at 250 nM and suppressing HNSCC viability at 500 nM. In summary our lead PROTAC effectively targeted LZK for proteasomal degradation and inhibited oncogenic activity in HNSCC cell lines with amplified LZK.

发现用于治疗头颈癌的LZK蛋白激酶的强效和选择性PROTACs。
亮氨酸拉链激酶(LZK)在20%的头颈部鳞状细胞癌(HNSCC)病例中过表达,并已成为该癌症亚型的有希望的治疗靶点。LZK分别通过激酶依赖性和非依赖性稳定c-MYC和GOF-p53来促进HNSCC的存活和增殖。在此,我们利用proteolysis-targeting chimera (PROTAC)技术,通过调节LZK-targeting PROTAC- 21a的LZK战斗部的连接区域,开发了一系列新的LZK降解剂。在合成和测试的27个PROTACs中,发现PROTAC 17是最有效的,在250 nM处降解LZK,在500 nM处抑制HNSCC活力。总之,我们的先导药物PROTAC有效地靶向LZK降解蛋白酶体,并抑制具有扩增LZK的HNSCC细胞系的致癌活性。
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来源期刊
Journal of Biological Chemistry
Journal of Biological Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry
自引率
4.20%
发文量
1233
期刊介绍: The Journal of Biological Chemistry welcomes high-quality science that seeks to elucidate the molecular and cellular basis of biological processes. Papers published in JBC can therefore fall under the umbrellas of not only biological chemistry, chemical biology, or biochemistry, but also allied disciplines such as biophysics, systems biology, RNA biology, immunology, microbiology, neurobiology, epigenetics, computational biology, ’omics, and many more. The outcome of our focus on papers that contribute novel and important mechanistic insights, rather than on a particular topic area, is that JBC is truly a melting pot for scientists across disciplines. In addition, JBC welcomes papers that describe methods that will help scientists push their biochemical inquiries forward and resources that will be of use to the research community.
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