4.7 Review

Clinical considerations for the design of PROTACs in cancer

Journal

MOLECULAR CANCER
Volume 21, Issue 1, Pages -

Publisher

BMC
DOI: 10.1186/s12943-022-01535-7

Keywords

PROTAC; New therapies; Clinical approach; Protein of interest

Funding

  1. Instituto de Salud Carlos III [PI19/00808]
  2. ACEPAIN
  3. Diputacion de Albacete
  4. CIBERONC
  5. CRIS Cancer Foundation
  6. European Community through the regional development funding program (FEDER)
  7. Spanish Ministry of Science and Innovation [IJC2019-041728-1]

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The development of protein degradation drugs (PROTACs) is of great importance in cancer treatment. By selecting the appropriate proteins as degradation targets and ubiquitin ligases that are highly expressed in tumor cells but not in normal tissues, the efficacy of treatment can be enhanced while minimizing toxicity.
Degradation of targeted proteins using proteolysis targeting chimeras (PROTACs) has gained momentum. A PROTAC is a bifunctional molecule that consists of three parts: a ligand that interacts with the protein to be degraded, another ligand that binds to an E3 ubiquitin ligase and a linker that connects both. Identification of the right proteins as targets to be degraded and a ligase that is highly expressed in tumors compare with normal tissue is mandatory, as can augment efficacy reducing toxicity. In this article we review the current development stage of PROTACs in cancer to categorize the best PROTAC construction. Targets including BCL2, CDK4 and MCL1 were highly expressed in all tumors; MCL1 was significantly increased in breast cancer and lung adenocarcinoma and CDK4 in colon adenocarcinoma. Degradation of CDK9, AURKA or PLK1, followed by BCL2, MCL1, PTPN11, BRD4, PTK2, showed a high dependency. Most ligases evaluated were not highly present in tumors except for MDM2 in breast, lung, prostate and gastric cancer. In non-transformed tissue MDM2 was the most abundant ligase, followed by cIAP and CRBN, and those with low expression included XIAP and VHL. MDM2 ligase coupled with inhibitors of the targets BCL2, BRD4, CDK9, PLK1 and MCL1 in stomach tumor, and MDM2 with PIK3C3 inhibitors in breast cancer, seems to be the best therapeutic strategy. Our results suggest potential options for the design of PROTACS in specific medical indications.

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