Structure-based discovery of SIAIS001 as an oral bioavailability ALK degrader constructed from Alectinib

Chaowei Ren; Ning Sun; Ying Kong; Xiaojuan Qu; Haixia Liu; Hui Zhong; Xiaoling Song; Xiaobao Yang; Biao Jiang

doi:10.1016/j.ejmech.2021.113335

Structure-based discovery of SIAIS001 as an oral bioavailability ALK degrader constructed from Alectinib

Eur J Med Chem. 2021 May 5:217:113335. doi: 10.1016/j.ejmech.2021.113335. Epub 2021 Mar 11.

Authors

Chaowei Ren¹, Ning Sun², Ying Kong³, Xiaojuan Qu¹, Haixia Liu⁴, Hui Zhong⁵, Xiaoling Song⁶, Xiaobao Yang⁷, Biao Jiang⁸

Affiliations

¹ Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
² Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China.
³ Jing Medicine Technology (Shanghai), Ltd., Y building230 Haike Road, Shanghai, 201210, China.
⁴ Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; School of Physical Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
⁵ Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; Changzhou University, Changzhou, Jiangsu, 213164, China.
⁶ Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China. Electronic address: songxl@shanghaitech.edu.cn.
⁷ Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China. Electronic address: yangxb@shanghaitech.edu.cn.
⁸ Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China. Electronic address: jiangbiao@shanghaitech.edu.cn.

PMID: 33751979
DOI: 10.1016/j.ejmech.2021.113335

Abstract

Fusion proteins of the anaplastic lymphoma kinase (ALK) are promising therapeutic targets for cancer and other human diseases, especially for non-small cell lung cancer (NSCLC) and anaplastic large-cell lymphomas (ALCLs). We described herein a structure-based design, synthesis, and evaluation of ALK PROTACs (proteolysis-targeting chimeras) based on Alectinib as the warhead. We firstly screened CRBN ligands as the E3 ligase moiety, then obtained a series of potent ALK degraders based on different CRBN ligands, exemplified by SIAIS091 and SIAIS001 with lenalidomide/thalidomide-based linkers. Both of them induced effective ALK degradation at low nanomolar concentrations in cells, and showed much better growth inhibition effects than Alectinib. SIAIS091 or SIAIS001 also promoted cell cycle arrest in G1/S phase. Finally, SIAIS001 exhibited good oral bioavailability in Pharmacokinetics study.

Keywords: Alectinib; Anaplastic large-cell lymphomas; Anaplastic lymphoma kinase; CRBN; Oral bioavailability; Proteolysis targeting chimeras.

MeSH terms

Administration, Oral
Anaplastic Lymphoma Kinase / antagonists & inhibitors*
Anaplastic Lymphoma Kinase / metabolism
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Biological Availability
Carbazoles / chemistry
Carbazoles / pharmacology*
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Non-Small-Cell Lung / pathology
Cell Cycle Checkpoints / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Molecular Structure
Piperidines / chemistry
Piperidines / pharmacology*
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Carbazoles
Piperidines
Protein Kinase Inhibitors
ALK protein, human
Anaplastic Lymphoma Kinase
alectinib