Proteolysis targeting chimeras (PROTACs) in cancer therapy
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REVIEW
Open Access
Proteolysis targeting chimeras (PROTACs) in cancer therapy Alberto Ocaña1,2,3*
and Atanasio Pandiella2,4
Abstract Exploitation of the protein degradation machinery as a therapeutic strategy to degrade oncogenic proteins is experiencing revolutionary advances with the development of proteolysis targeting chimeras (PROTACs). PROTACs are heterobifunctional structures consisting of a ligand that binds a protein to be degraded and a ligand for an E3 ubiquitin ligase. The bridging between the protein of interest and the E3 ligase mediated by the PROTAC facilitates ubiquitination of the protein and its proteasomal degradation. In this review we discuss the molecular medicine behind PROTAC mechanism of action, with special emphasis on recent developments and their potential translation to the clinical setting. Keywords: PROTACs, BET inhibitors, Proteasome, Ubiquitination, Protein degradation
Novel druggable vulnerabilities in cancer Cancer is a multistep process in which genomic and epigenomic alterations lead to the abnormal cellular proliferation and dissemination [1]. Identification of molecular vulnerabilities that maintain the oncogenic phenotype has attracted major interest as the first step for the development of novel therapeutics [2]. A disbalance in the homeostasis of the protein production can be an oncogenic vulnerability in some tumors [3, 4], as demonstrated by the arrival of proteasome inhibitors to the oncology clinic [3, 4]. A novel class of agents that exploit the cellular protein degradation machinery with therapeutic purposes are the Proteolysis Targeting Chimeras or PROTACs [5]. These compounds can be used to facilitate proteasomal degradation of proteins that participate in the prooncogenic process. Importantly, PROTACs can be used to target a variety of proteins, including those with enzymatic activity or others difficult to target, such as those with scaffolding * Correspondence: [email protected]; [email protected] 1 Experimental Therapeutics Unit, Medical Oncology Department, Hospital Clínico San Carlos, and IdISSC, Madrid, Spain 2 Centro de Investigación Biomédica en Red Oncología (CIBERONC), Madrid, Spain Full list of author information is available at the end of the article
properties [3]. That is the case of transcription factors (TFs) (see glossary), which represent a large family of proteins against which very limited therapeutic options exist [6, 7]. TFs, as well as nuclear receptors, have been involved in the oncogenic generation of several malignancies. In fact, genomic alterations in c-MYC, FOXO1 or the androgen receptor (AR) have been described in neuroblastoma, breast or prostate cancer, respectively [6, 8]. A therapeutic strategy that has been contemplated is the reduction of the expression of these proteins by inducing their degradation. In this context, two PROTACs targeting the AR and estrogen receptor (ER) have reached the clinical setting being explored in two phase I studies in prostate and estrogen receptor-positive breast cancer [9].
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