Design, Synthesis, and Biological Evaluation of mTOR-Targeting PROTACs Based on MLN0128 and Pomalidomide

Abstract

Chemical and Pharmaceutical Bulletin Advance PublicationmTOR is an effective anti-tumor drug target. Several mTOR kinase inhibitors have entered clinical research, but there are still challenges of potential toxicity. As a new type of targeted drug, proteolysis targeting chimeras (PROTACs) have features of low dosage and low toxicity. However, this approach has been rarely reported to involve mTOR degradation. In this study, the mTOR kinase inhibitor MLN0128 was used as the ligand to the protein of interest and conjugated with pomalidomide by diverse intermediate linkage chains. Several potential small molecule PROTACs for the degradation of mTOR were designed and synthesized. PROTAC compounds exhibited mTOR inhibitory activity and suppressed MCF-7 cell proliferation. The representative compound P1 could inhibit the expression of mTOR downstream proteins and the growth of cancer cells by inducing autophagy but not affecting the cell cycle and not inducing apoptosis.

Rapamycin <i>vs</i> TORin-1 or Gleevec <i>vs</i> Nilotinib: Simple chemical evolution that converts PAK1-blockers to TOR-blockers or <i>vice versa</i>?

“…In other words, pomalidomide is simply a PAK1blocker, while thalidomide is a "CRBN/TOR" inhibitor as well as a PAK1-blocker. Very recently (2023), a Chinese group developed a potent TOR-specific PROTAC (protein-targeting chimera) by combining "POM" and a TOR-binding ligand called "MLN0128" (49), perhaps for their great fun, or at least proving that pomalidomide alone never inhibits (or binds) TOR. By the way, POM is 10 times more potent than thalidomide and lenalidomide for therapy of a hematological cancer called MM clinically, most likely because pomalidomide is no longer immune-suppressive (50).…”

PROTACs: A novel strategy for cancer drug discovery and development

“…cIAP1, cIAP2, and X‐chromosome‐linked IAP (XIAP) belong to the family of antiapoptotic proteins that play a critical role in the control of apoptotic machinery 354–361 . The widespread use of IAPs as an E3 ligase in TPD has drawn much attention from scientists in both academia and industry 362–368 .…”

“…cIAP1, cIAP2, and X‐chromosome‐linked IAP (XIAP) belong to the family of antiapoptotic proteins that play a critical role in the control of apoptotic machinery. 354 , 355 , 356 , 357 , 358 , 359 , 360 , 361 The widespread use of IAPs as an E3 ligase in TPD has drawn much attention from scientists in both academia and industry. 362 , 363 , 364 , 365 , 366 , 367 , 368 Correspondingly, many IAPs inhibitors were discovered and applied in the design of PROTAC degraders.…”