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

Targeting Cysteine Located Outside the Active Site: An Effective Strategy for Covalent ALKi Design

Potent inhibitors of ALK are highly desired because of the occurrence of drug resistance. We herein firstly report the development of a rationally designed inhibitor, Con B-1, which can covalently bind to Cys1259, a cysteine located outside the ALK active site by linking a warhead with Ceritinib through a 2,2′-Oxybis(ethylamine) linker. The in vitro and in vivo assays showed ConB-1 is a potent selective ALKi with low toxicity to normal cells. In addition, the molecule showed significant improvement of anticancer activities and potential antidrug resistant activity compared with Ceritinib, demonstrating the covalent inhibitor of ALK can be a promising drug candidate for the treatment of NSCLC. This work may provide a novel perspective on the design of covalent inhibitors. READ ARTICLE

Journal of Medicinal Chemistry DOI:10.1021/acs.jmedchem.0c01707

Authors: Guoyi Yan, Xinxin Zhong, Chunlan Pu, Lin Yue, Huifang Shan, Suke Lan, Meng Zhou, Xueyan Hou, Jie Yang, Deyu Li, Shilong Fan, and Rui Li

Pre-ClinicalKirk SmithJanuary 20, 2021Cells, Inhibitors, Inhibition, Peptides and proteins, Molecules

Discovery of CJ-2360 as a Potent and Orally Active Inhibitor of Anaplastic Lymphoma Kinase Capable of Achieving Complete Tumor Regression

We report herein the discovery of a class of potent small-molecule inhibitors of anaplastic lymphoma kinase (ALK) containing a fused indoloquinoline scaffold. The most promising compound CJ-2360 has an IC50 value of 2.2 nM against wild-type ALK and low-nanomolar potency against several clinically reported ALK mutants. This compound is capable of achieving complete tumor regression in the ALK-positive KARPAS-299 xenograft model with oral administration in mice. CJ-2360 represents a promising ALK inhibitor for advanced preclinical development. READ ARTICLE

Journal of Medicinal Chemistry DOI:10.1021/acs.jmedchem.0c01550

Authors: Jianyong Chen, Yunlong Zhou, Xuyuan Dong, Liu Liu, Longchuan Bai, Donna McEachern, Sally Przybranowski, Chao-Yie Yang, Jeanne Stuckey, Xiaoqin Li, Bo Wen, Ting Zhao, Siwei Sun, Duxin Sun, Lingling Jiao, Yu Jing, Ming Guo, Dajun Yang, and Shaomeng Wang

Pre-ClinicalKirk SmithNovember 13, 2020Rodent models, Inhibitors, Inhibition, Peptides and proteins, Tumors

MPRIP-ALK, a Novel ALK Rearrangement That Responds to ALK Inhibition in NSCLC

Oncogenic rearrangements of the ALK receptor tyrosine kinase (ALK) gene are detected in approximately 7% of NSCLC patients.1 However, novel partner genes for ALK fusion and their clinical significance are not fully defined. Herein we describe the first case of ALK fusion with the myosin phosphatase Rho interacting protein gene (MPRIP) via next-generation sequencing (NGS), whose oncogenicity was further validated in vitro. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.02.030

Authors: Wenfeng Fang, Jiadi Gan, Shaodong Hong, Feng Lu, Li Zhang.

EditorialKirk SmithJuly 1, 2019MPRIP-ALK, ALK, Inhibition, NSCLC

Designing Dual Inhibitors of Anaplastic Lymphoma Kinase (ALK) and Bromodomain-4 (BRD4) by Tuning Kinase Selectivity

Concomitant inhibition of anaplastic lymphoma kinase (ALK) and bromodomain-4 (BRD4) is a potential therapeutic strategy for targeting two key oncogenic drivers that co-segregate in a significant fraction of high-risk neuroblastoma patients, mutation of ALK and amplification of MYCN. Starting from known dual polo-like kinase (PLK)-1–BRD4 inhibitor BI-2536, we employed structure-based design to redesign this series toward compounds with a dual ALK–BRD4 profile. These efforts led to compound (R)-2-((2-ethoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-7-ethyl-5-methyl-8-((4-methylthiophen-2-yl)methyl)-7,8-dihydropteridin-6(5H)-one (16k) demonstrating improved ALK activity and significantly reduced PLK-1 activity, while maintaining BRD4 activity and overall kinome selectivity. We demonstrate the compounds’ on-target engageme READ ARTICLE

Journal of Medicinal Chemistry DOI:10.1021/acs.jmedchem.8b01947

Authors: Ellen Watts, David Heidenreich, Elizabeth Tucker, Monika Raab, Klaus Strebhardt, Louis Chesler, Stefan Knapp, Benjamin Bellenie, and Swen Hoelder

Pre-ClinicalKirk SmithFebruary 21, 2019Chemical structure, Inhibitors, Inhibition, Peptides and proteins, Selectivity

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