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

Abstract

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.

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

“…19 ) also based on Alectinib. 128 The difference from Jiang group was that the E3 ligase ligand they used was pomalidomide, while Jiang group was lenalidomide. They found degrader 71 had the best ALK degradation activity, highest ALK binding affinity and best antiproliferative activity in such ALK-dependent cell lines as H3122 cells and Karpas 299 cells, whose DC 50 were 27.4 nM, 116.5 nM and IC 50 were 62 nM, 42 nM.…”

E3 ligase ligand chemistries: from building blocks to protein degraders

“…57 In addition, S N Ar with 6 is a common strategy to synthesise void POI ligand–E3 ligand dimers. 58–60 For instance, chemists from Nathanael Gray's group reacted the piperazine handle of the cyclin-dependent kinases (CDK) 4/6 inhibitor palbociclib with 4-fluorothalidomide (Example 9). However, this reaction sequence is unfavourable if one aims to generate an in-house E3 ligand–linker library for initial PROTAC screening campaigns.…”

Holistic View of ALK TKI Resistance in ALK-Positive Anaplastic Large Cell Lymphoma

“…PROTAC directly targets and degrades proteins and is unaffected by ALK point mutations; this explains how PROTAC designed with alectinib/brigatinib can degrade the ALK G1202R mutant, which is resistant to the drugs themselves. PROTAC designed with alectinib as the ligand was more effective than alectinib in ALK+ ALCL patients and enhanced ALK degradation ( 115 – 117 ). ARV-110, the first PROTAC drug targeting the androgen receptor, has been used in patients with metastatic debulking-resistant prostate cancer with promising results ( 118 ).…”