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.

Keywords: Clinical approach; New therapies; PROTAC; Protein of interest.

Fig. 1

Classification of the number of scientific articles per target (A), function of the target (B) and the type of ligase ligand (C). D Representation of the targets and the function in which they are involved. E Compounds and ligases linked to each target

Fig. 2

Effect of target silencing on different tumor types. A Effect of silencing by both CRISPR and RNAi on different cell lines from several tumor types. Data from DepMap portal. Common essential: A gene which, in a large, pan-cancer screen, ranks in the top X most depleting genes in at least 90% of cell lines. X is chosen empirically using the minimum of the distribution of gene ranks in their 90th percentile least depleting lines. Strongly selective: A gene whose dependency is at least 100 times more likely to have been sampled from a skewed distribution than a normal distribution. B CERES and DEMETER2 dependency score of each gene in the five tumors with the highest incidence including breast, lung, colorectal, prostate and gastric cancer. A score of 0 indicates that a gene is not essential, and a score of -1 is comparable to the median of all pan-essential genes

Fig. 3

A RNA expression in TPM of targets in tumoral tissues with the highest incidence according to GEPIA2. B RNA expression in TPM of ligands in tumoral tissues with the highest incidence according to GEPIA2. C Targets and ligases with TPM > 32. BRCA: Breast Invasive Carcinoma, COAD: Colon adenocarcinoma, LUAD: Lung adenocarcinoma, PRAD: Prostate adenocarcinoma, STAD: Stomach adenocarcinoma

Fig. 4

RNA expression in TPM of targets and ligases in several tissues. RNA expression in TPM of targets (A) and ligases (B) according to GEPIA2 data in several normal tissues. C Number of normal tissues in which ligases and targets are highly increased. D Number of targets, and ligases, with an expression greater than 32 TPM in the different tissues. E Ligases and targets expressed more than 32 TPM in tumor tissue, but less than 32 TPM in normal tissue. STAD: Stomach adenocarcinoma. BRCA: Breast invasive carcinoma