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Published on: February 6, 2015
Clinical considerations for the design of PROTACs in cancer
Cristina Nieto-Jiménez1, Esther Cabañas Morafraile2,3, Carlos Alonso-Moreno4,5
1Experimental Therapeutics Unit, Medical Oncology Department, Hospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria (IdISSC) and CIBERONC, 28040, Madrid, Spain. cnietoj@salud.madrid.org.
Abstract:
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.
Insights
Proteolysis targeting chimeras (PROTACs) offer a novel cancer therapy by degrading target proteins. Combining specific target ligands with E3 ligase ligands, like MDM2, shows promise for improved efficacy and reduced toxicity.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Proteolysis targeting chimeras (PROTACs) are bifunctional molecules designed for targeted protein degradation.
- PROTACs comprise a target protein ligand, an E3 ubiquitin ligase ligand, and a linker.
- Optimizing PROTACs requires selecting appropriate protein targets and E3 ligases with differential expression in tumors versus normal tissues to enhance efficacy and reduce toxicity.
Purpose of the Study:
- To review the current development of PROTACs in cancer therapy.
- To categorize optimal PROTAC constructions based on target proteins and E3 ligase expression.
- To identify promising therapeutic strategies for specific cancer types.
Main Methods:
- Literature review of PROTAC development in cancer.
- Analysis of target protein expression (BCL2, CDK4, MCL1, CDK9, AURKA, PLK1, PTPN11, BRD4, PTK2) across various tumors.
- Evaluation of E3 ligase expression (MDM2, cIAP, CRBN, XIAP, VHL) in tumor and non-transformed tissues.
Main Results:
- BCL2, CDK4, and MCL1 are highly expressed in tumors, with specific increases in breast, lung, and colon cancers.
- High dependency on degradation was observed for CDK9, AURKA, PLK1, BCL2, MCL1, PTPN11, BRD4, PTK2.
- MDM2 was the most abundant E3 ligase in several tumor types (breast, lung, prostate, gastric) and also in normal tissue, while XIAP and VHL showed low expression.
- MDM2 ligase coupled with BCL2, BRD4, CDK9, PLK1, MCL1 inhibitors in stomach tumors, and MDM2 with PIK3C3 inhibitors in breast cancer, represent promising strategies.
Conclusions:
- PROTAC design requires careful selection of target proteins and E3 ligases based on differential expression patterns.
- MDM2 ligase, particularly when combined with specific inhibitors for targets like BCL2 or PIK3C3, presents a viable therapeutic strategy for certain cancers.
- The findings suggest potential PROTAC design options for specific medical indications, warranting further investigation.
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