Discovery of a Brigatinib Degrader SIAIS164018 with Destroying Metastasis-Related Oncoproteins and a Reshuffling Kinome Profile

Proteolysis-targeting chimera (PROTAC) is an attractive technology in drug discovery. Canonically, targets act as a basic starting point in the most previous PROTAC design. Here, we designed degraders considering from the view of clinical benefits. With this novel design, Brigatinib was turned into a degrader SIAIS164018 and endowed with unique features. First, SIAIS164018 could degrade not only ALK fusion proteins in activating or G1202R-mutated form but also mutant EGFR with L858R + T790M, which are two most important targets in non-small-cell lung cancer. Second, SIAIS164018 strongly inhibited cell migration and invasion of Calu-1 and MDA-MB-231. Third and surprisingly, SIAIS164018 degrades several important oncoproteins involved in metastasis such as FAK, PYK2, and PTK6. Interestingly, SIAIS164018 reshuffled the kinome ranking profile when compared to Brigatinib. Finally, SIAIS164018 is orally bioavailable and well tolerated in vivo. SIAIS164018 is an enlightening degrader for us to excavate the charm of protein degradation. READ ARTICLE

Journal of Medicinal Chemistry DOI:10.1021/acs.jmedchem.1c00373

Authors: Chaowei Ren, Ning Sun, Haixia Liu, Ying Kong, Renhong Sun, Xing Qiu, Jinju Chen, Yan Li, Jianshui Zhang, Yuedong Zhou, Hui Zhong, Qianqian Yin

Development of Alectinib-Based PROTACs as Novel Potent Degraders of Anaplastic Lymphoma Kinase (ALK)

A series of novel anaplastic lymphoma kinase (ALK) degraders were designed and synthesized based on proteolysis-targeting chimera (PROTAC) technology by linking two alectinib analogs (36 and 37) with pomalidomide through linkers of different lengths and types. The most promising degrader 17 possessed a high ALK-binding affinity and potent antiproliferative activity in the ALK-dependent cell lines and did not exhibit obvious cytotoxicity in ALK fusion-negative cells. More importantly, the efficacy of compound 17 in a Karpas 299 xenograft mouse model was further evaluated based on its ALK-sustained degradation ability in vivo. The reduction in tumor weight in the compound 17-treated group (10 mg/kg/day, I.V.) reached 75.82%, while alectinib reduced tumor weight by 63.82% at a dose of 20 mg/kg/day (P.O.). Taken together, our findings suggest that alectinib-based PROTACs associated with the degradation of ALK may have promising beneficial effects for treating ALK-driven malignancies. READ ARTICLE

Journal of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c00270

Authors: Shaowen Xie, Yuan Sun, Yulin Liu, Xinnan Li, Xinuo Li, Wenyi Zhong, Feiyan Zhan, Jingjie Zhu, Hong Yao, Dong-Hua Yang, Zhe-Sheng Chen, Jinyi Xu and Shengtao Xu

Pre-Clinical, group4Kirk SmithJune 28, 2021Degradation, Inhibitors, Inhibition, PROTAC, ALK

Induced protein degradation of anaplastic lymphoma kinase (ALK) by proteolysis targeting chimera (PROTAC)

Recently, proteolysis targeting chimera (PROTAC) technology is highlighted in drug discovery area as a new therapeutic approach. PROTAC as a heterobifunctional molecule is comprised of two ligands, which recruit target protein and E3 ligase, respectively. To degrade the anaplastic lymphoma kinase (ALK) fusion protein, such as NPM-ALK or EML4-ALK, we generated several ALK-PROTAC molecules consisted of ceritinib, one of the ALK inhibitors, and ligand of von Hippel-Lindau (VHL) E3 ligase. Among these molecules, TD-004 effectively induced ALK degradation and inhibited the growth of ALK fusion positive cell lines, SU-DHL-1 and H3122. We also confirmed that TD-004 significantly reduced the tumor growth in H3122 xenograft model. READ ARTICLE

Biochemical and Biophysical Research Communications DOI:10.1016/j.bbrc.2018.09.169

Authors: Chung Hyo Kanga, Dong Ho Lee, Chong Ock Lee, Jae Du Ha, Chi Hoon Park, Jong Yeon Hwang

Chemically Induced Degradation of Anaplastic Lymphoma Kinase (ALK)

We present the development of the first small molecule degraders that can induce anaplastic lymphoma kinase (ALK) degradation, including in non-small-cell lung cancer (NSCLC), anaplastic large-cell lymphoma (ALCL), and neuroblastoma (NB) cell lines. These degraders were developed through conjugation of known pyrimidine-based ALK inhibitors, TAE684 or LDK378, and the cereblon ligand pomalidomide. We demonstrate that in some cell types degrader potency is compromised by expression of drug transporter ABCB1. In addition, proteomic profiling demonstrated that these compounds also promote the degradation of additional kinases including PTK2 (FAK), Aurora A, FER, and RPS6KA1 (RSK1). READ ARTICLE

Journal of Medicinal Chemistry DOI:10.1021/acs.jmedchem.7b01655

Authors: Chelsea E. Powell, Yang Gao, Li Tan, Katherine A. Donovan, Radosław P. Nowak, Amanda Loehr, Magda Bahcall, Eric S. Fischer, Pasi A. Jänne, Rani E. George, and Nathanael S. Gray