Clinical considerations for the design of PROTACs in cancer

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.

New Opportunities for the Utilization of the Sulfoximine Group in Medicinal Chemistry from the Drug Designer's Perspective**

“…Targeted protein degradation using proteolysis targeting chimeras (PROTACs) has gained considerable momentum as a novel therapeutic modality in drug discovery [56] . PROTACs are heterobifunctional molecules which consist of three parts: a ligand to bind to an E3 ubiquitin ligase and a second ligand to bind to the protein of interest, connected by a chemical linker [57] . Selective CDK9 inhibitor atuveciclib ( 20 , see Figure 8) was recently utilized for the development of a series of selective CDK9 degraders with enhanced antiproliferative activity [58] .…”

“…[56] PROTACs are heterobifunctional molecules which consist of three parts: a ligand to bind to an E3 ubiquitin ligase and a second ligand to bind to the protein of interest, connected by a chemical linker. [57] Selective CDK9 inhibitor atuveciclib (20, see Figure 8) was recently utilized for the development of a series of selective CDK9 degraders with enhanced antiproliferative activity. [58] In the CDK9/atuveciclib complex, the sulfoximine group is directed to the exit of the ATP binding pocket [28] enabling the utilization of the sulfoximine NH for the introduction of various linkers to the E3 ligase binding moiety, similar to the design strategy of the CDK9 ADCs at Bayer AG (see above).…”

Targeting Protein Degradation Pathways in Tumors: Focusing on their Role in Hematological Malignancies

“…The rapid development of synthetic molecular glues followed these initial studies and offered new options for the modulation of protein–protein interactions, including tagging proteins for degradation; for a review see [ 53 ]. Proteolysis-targeting chimeras (PROTACs) emerged as a novel method for targeting proteins of interest (POIs) for subsequent degradation [ 54 , 55 ]. These are small bifunctional molecules that better enable the natural cellular ATP-dependent ubiquitin proteasome system (UPS) to break down the target proteins.…”

Sulfoximines in Medicinal Chemistry: Emerging Trends and Opportunities from the Drug Designer’s Perspective

“…[54] PROTACs are heterobifunctional molecules which consist of three parts: a ligand to bind to an E3 ubiquitin ligase and a second ligand to bind to the protein of interest, connected by a chemical linker. [55] Selective CDK9 inhibitor atuveciclib (20, see Figure 8) was recently utilized for the development of a series of selective CDK9 degraders with enhanced antiproliferative activity. [56] In the CDK9/atuveciclib complex, the sulfoximine group is directed to the exit of the ATP binding pocket [26] enabling the utilization of the sulfoximine NH for the introduction of various linkers to the E3 ligase binding moiety, similar to the design strategy of the CDK9 ADCs at Bayer AG (vide supra).…”