2. Academic Validation
  3. Drug Discovery Targeting Anaplastic Lymphoma Kinase (ALK)

Drug Discovery Targeting Anaplastic Lymphoma Kinase (ALK)

  • J Med Chem. 2019 Dec 26;62(24):10927-10954. doi: 10.1021/acs.jmedchem.9b00446.
Xiaotian Kong 1 2,  Peichen Pan 1,  Huiyong Sun 1,  Hongguang Xia 3,  Xuwen Wang 1,  Youyong Li 2,  Tingjun Hou 1
Affiliations

Affiliations

  • 1 Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , Zhejiang 310058 , China.
  • 2 Institute of Functional Nano and Soft Materials (FUNSOM) , Soochow University , Suzhou , Jiangsu 215123 , China.
  • 3 Department of Biochemistry & Research Center of Clinical Pharmacy of the First Affiliated Hospital , Zhejiang University , Hangzhou 310058 , China.
PMID: 31419130 DOI: 10.1021/acs.jmedchem.9b00446
Abstract

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.

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