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

Identification of novel bioactive molecules from garlic bulbs: A special effort to determine the anticancer potential against lung cancer with targeted drugs

... Garlic is used in the treatment of various ailments such as cancer, diabetes and cardiovascular diseases. The present study aims to explore the plausible mechanisms of the selected phytocompounds as potential inhibitors against the known drug targets of non-small-cell lung cancer (NSCLC)... The result of this study suggest that these identified phytocompounds from garlic would serve as promising leads for the development of lead molecules to design new multi-targeting drugs to address the different clinical forms of NSCLC. READ ARTICLE

Saudi Journal of Biological Sciences DOI:10.1016/j.sjbs.2020.09.041

Authors: R. Padmini, V. Uma Maheshwari, P.Saravanan, Keun Woo Lee, M. Razia, Mona S. Alwahibi, B. Ravindran, Mohamed Soliman Elshikh, Young Ock Kim, Hyungsuk Kim, Hak-Jae Kim

Case StudyKirk SmithDecember 1, 2020Docking, Garlic, Inhibitors, Lung cancer, Molecular dynamics simulations

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

HSR20-084: Real-World Adherence and Persistence of ALK Inhibitors in Non-Small Cell Lung Cancer (NSCLC)

Background: About 5% of NSCLC cases present with anaplastic lymphoma kinase (ALK) fusions and are candidates for an ALK tyrosine kinase inhibitor (ALKi). Evidence on real-world adherence and persistence of ALKi is limited. Objectives: Estimate adherence and persistence of in NSCLC. Results: This study analyzed 1482 patients whose first ALKi was alectinib or crizotinib (n=445 and 1037, respectively) and 880 patients with subsequent ALKis (604 alectinib, 142 brigatinib, 134 ceritinib). Adherence during treatment period (95-97%) and proportions of MPR ³0.8 (92-95%) were similar across all ALKis. Real-world median time to discontinuation was 27.4 vs 8.9 months for alectinib vs crizotinib in the first ALKi cohort. Patients using alectinib as first ALKi were 46% less likely to discontinue ALKi than crizotinib patients (adjusted hazard ratio (aHR) [95% CI]: 0.54 [0.44-0.65]). For subsequent ALKi use, the risk of discontinuation for alectinib was 64% lower vs ceritinib (aHR [95% CI]: 0.36 [0.2..... READ ARTICLE

Journal of the National Comprehensive Cancer Network DOI:10.6004/jnccn.2019.7501

Authors: Ganti, A. K., Ogale, S., Yang, E., & Wong, W.

Real-World OutcomesKirk SmithMarch 20, 2020Persistence, Inhibitors, Alectinib

Drug Discovery Targeting Anaplastic Lymphoma Kinase (ALK)

As a receptor tyrosine kinase of insulin receptor (IR) subfamily, anaplastic lymphoma kinase (ALK) has been validated to play important roles in various cancers, especially anaplastic large cell lymphoma (ALCL), nonsmall cell lung cancer (NSCLC), and neuroblastomas. Currently, five small-molecule inhibitors of ALK, including Crizotinib, Ceritinib, Alectinib, Brigatinib, and Lorlatinib, have been approved by the U.S. Food and Drug Administration (FDA) against ALK-positive NSCLCs. Novel type-I1/2 and type-II ALK inhibitors with improved kinase selectivity and enhanced capability to combat drug resistance have also been reported. Moreover, the "proteolysis targeting chimera" (PROTAC) technique has been successfully applied in developing ALK degraders, which opened a new avenue for targeted ALK therapies. This review provides an overview of the physiological and biological functions of ALK, the discovery and development of drugs targeting ALK by focusing on their chemotypes, activity, selectivity, and resistance as well as potential therapeutic strategies to overcome drug resistance. READ ARTICLE

Journal of Medicinal Chemistry DOI:10.1021/acs.jmedchem.9b00446

Authors: Kong X, Pan P, Sun H, Xia H, Wang X, Li Y, Hou T.

Pre-ClinicalKirk SmithAugust 16, 2019Drug resistance, Peptides and proteins, Genetics, Inhibitors

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

Discovery of (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922)...

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity. READ ARTICLE

Journal of Medicinal Chemistry DOI:10.1021/jm500261q

Authors: Ted W. Johnson, Paul F. Richardson, Simon Bailey, Alexei Brooun, Benjamin J. Burke, Michael R. Collins, J. Jean Cui, Judith G. Deal, Ya-Li Deng, Dac Dinh, Lars D. Engstrom, Mingying He, Jacqui Hoffman, Robert L. Hoffman, Qinhua Huang, Robert S. Kania, John C. Kath, Hieu Lam, Justine L. Lam, Phuong T. Le, Laura Lingardo, Wei Liu, Michele McTigue, Cynthia L. Palmer, Neal W. Sach, Tod Smeal, Graham L. Smith, Albert E. Stewart, Sergei Timofeevski, Huichun Zhu, Jinjiang Zhu, Helen Y. Zou, and Martin P. Edwards