Proteolysis targeting chimera

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TL 12-186, a thalidomide-based PROTAC targeting the protein GSPT1, a translation termination factor TL 12-186 skeletal.svg
TL 12-186, a thalidomide-based PROTAC targeting the protein GSPT1, a translation termination factor

A proteolysis targeting chimera (PROTAC) [2] is a molecule that can remove specific unwanted proteins. Rather than acting as a conventional enzyme inhibitor, a PROTAC works by inducing selective intracellular proteolysis. A heterobifunctional molecule with two active domains and a linker, PROTACs consist of two covalently linked protein-binding molecules: one capable of engaging an E3 ubiquitin ligase, and another that binds to a target protein meant for degradation. Recruitment of the E3 ligase to the target protein results in ubiquitination and subsequent degradation of the target protein via the proteasome. Because PROTACs need only to bind their targets with high selectivity (rather than inhibit the target protein's enzymatic activity), there are currently many efforts to retool previously ineffective inhibitor molecules as PROTACs for next-generation drugs. [3] [4]

Contents

Initially described by Kathleen Sakamoto, Craig Crews and Ray Deshaies in 2001, [5] the PROTAC technology has been applied by a number of drug discovery labs using various E3 ligases, [6] including pVHL, [7] [8] [9] CRBN, [10] [11] Mdm2, [12] beta-TrCP1, [5] DCAF11, [13] [14] DCAF15, [15] DCAF16, [15] RNF114, [15] and c-IAP1. [16] Yale University licensed the PROTAC technology to Arvinas in 2013–14. [17] [18]

In 2019, Arvinas put two PROTACs into clinical trials: bavdegalutamide (ARV-110), an androgen receptor degrader, and vepdegestrant (ARV-471), an estrogen receptor degrader. [19] [20] In 2021, Arvinas put a second androgen receptor PROTAC, Luxdegalutamide (ARV-766), into the clinic. [21]

Mechanism of action

Mechanism. E1, E2, E3: ubiquitination enzymes; Ub = ubiquitin; target = protein to be degraded Proteolysis targeting chimera mechanism.svg
Mechanism. E1, E2, E3: ubiquitination enzymes; Ub = ubiquitin; target = protein to be degraded

PROTACs achieve degradation through "hijacking" the cell's ubiquitin–proteasome system (UPS) by bringing together the target protein and an E3 ligase. [22]

First, the E1 activates and conjugates the ubiquitin to the E2. [15] The E2 then forms a complex with the E3 ligase. The E3 ligase targets proteins and covalently attaches the ubiquitin to the protein of interest. [22] Eventually, after a ubiquitin chain is formed, the protein is recognized and degraded by the 26S proteasome. [19] PROTACs take advantage of this cellular system by putting the protein of interest in close proximity to the E3 ligase to catalyze degradation. [19]

Unlike traditional inhibitors, PROTACs have a catalytic mechanism, with the PROTAC itself being recycled after the target protein is degraded. [19]

Design and development

The protein targeting warhead, E3 ligase, and linker must all be considered for PROTAC development. Formation of a ternary complex between the protein of interest, PROTAC, and E3 ligase may be evaluated to characterize PROTAC activity because it often leads to ubiquitination and subsequent degradation of the targeted protein. [15] A hook effect is commonly observed with high concentrations of PROTACs due to the bifunctional nature of the degrader. [15]

Currently, pVHL and CRBN have been used in preclinical trials as E3 ligases. [15] However, there still remains hundreds of E3 ligases to be explored, with some giving the opportunity for cell specificity.

Benefits

Compared to traditional inhibitors, PROTACs display multiple benefits that make them desirable drug candidates. Due to their catalytic mechanism, PROTACs can be administered at lower doses compared to their inhibitor analogues, [20] though care needs to be taken in achieving oral bioavailability if administered by that route. [23] Some PROTACs have been shown to be more selective than their inhibitor analogues, reducing off-target effects. [20] PROTACs have the ability to target previously undruggable proteins, as they do not need to target catalytic pockets. [20] This also helps prevent mutation-driven drug resistance often found with enzymatic inhibitors.

PROTAC databases

Related Research Articles

<span class="mw-page-title-main">Proteasome</span> Protein complexes which degrade ubiquitin-tagged proteins by proteolysis

Proteasomes are protein complexes which degrade ubiquitin-tagged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.

<span class="mw-page-title-main">Ubiquitin</span> Regulatory protein found in most eukaryotic tissues

Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ubiquitously. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A.

<span class="mw-page-title-main">Ubiquitin ligase</span> Protein

A ubiquitin ligase is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate. In simple and more general terms, the ligase enables movement of ubiquitin from a ubiquitin carrier to another protein by some mechanism. The ubiquitin, once it reaches its destination, ends up being attached by an isopeptide bond to a lysine residue, which is part of the target protein. E3 ligases interact with both the target protein and the E2 enzyme, and so impart substrate specificity to the E2. Commonly, E3s polyubiquitinate their substrate with Lys48-linked chains of ubiquitin, targeting the substrate for destruction by the proteasome. However, many other types of linkages are possible and alter a protein's activity, interactions, or localization. Ubiquitination by E3 ligases regulates diverse areas such as cell trafficking, DNA repair, and signaling and is of profound importance in cell biology. E3 ligases are also key players in cell cycle control, mediating the degradation of cyclins, as well as cyclin dependent kinase inhibitor proteins. The human genome encodes over 600 putative E3 ligases, allowing for tremendous diversity in substrates.

<span class="mw-page-title-main">Mdm2</span> Protein-coding gene in humans

Mouse double minute 2 homolog (MDM2) also known as E3 ubiquitin-protein ligase Mdm2 is a protein that in humans is encoded by the MDM2 gene. Mdm2 is an important negative regulator of the p53 tumor suppressor. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain (TAD) of the p53 tumor suppressor and as an inhibitor of p53 transcriptional activation.

Ubiquitin-conjugating enzymes, also known as E2 enzymes and more rarely as ubiquitin-carrier enzymes, perform the second step in the ubiquitination reaction that targets a protein for degradation via the proteasome. The ubiquitination process covalently attaches ubiquitin, a short protein of 76 amino acids, to a lysine residue on the target protein. Once a protein has been tagged with one ubiquitin molecule, additional rounds of ubiquitination form a polyubiquitin chain that is recognized by the proteasome's 19S regulatory particle, triggering the ATP-dependent unfolding of the target protein that allows passage into the proteasome's 20S core particle, where proteases degrade the target into short peptide fragments for recycling by the cell.

<span class="mw-page-title-main">SKP2</span> Protein-coding gene in the species Homo sapiens

S-phase kinase-associated protein 2 is an enzyme that in humans is encoded by the SKP2 gene.

<span class="mw-page-title-main">PSMD2</span> Enzyme found in humans

26S proteasome non-ATPase regulatory subunit 2, also as known as 26S Proteasome Regulatory Subunit Rpn1, is an enzyme that in humans is encoded by the PSMD2 gene.

<span class="mw-page-title-main">Ubiquitin D</span> Protein-coding gene in the species Homo sapiens

Ubiquitin D is a protein that in humans is encoded by the UBD gene, also known as FAT10. UBD acts like ubiquitin, by covalently modifying proteins and tagging them for destruction in the proteasome.

<span class="mw-page-title-main">CUL4B</span> Protein-coding gene in humans

Cullin-4B is a protein that in humans is encoded by the CUL4B gene which is located on the X chromosome. CUL4B has high sequence similarity with CUL4A, with which it shares certain E3 ubiquitin ligase functions. CUL4B is largely expressed in the nucleus and regulates several key functions including: cell cycle progression, chromatin remodeling and neurological and placental development in mice. In humans, CUL4B has been implicated in X-linked intellectual disability and is frequently mutated in pancreatic adenocarcinomas and a small percentage of various lung cancers. Viruses such as HIV can also co-opt CUL4B-based complexes to promote viral pathogenesis. CUL4B complexes containing Cereblon are also targeted by the teratogenic drug thalidomide.

<span class="mw-page-title-main">CUL3</span> Protein-coding gene in humans

Cullin 3 is a protein that in humans is encoded by the CUL3 gene.

<span class="mw-page-title-main">UBE2D3</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-conjugating enzyme E2 D3 is a protein that in humans is encoded by the UBE2D3 gene.

<span class="mw-page-title-main">Cereblon</span> Protein in humans

Cereblon is a protein that in humans is encoded by the CRBN gene. The gene that encodes the cereblon protein is found on the human chromosome 3, on the short arm at position p26.3 from base pair 3,190,676 to base pair 3,221,394. CRBN orthologs are highly conserved from plants to humans.

<span class="mw-page-title-main">JQ1</span> Chemical compound

JQ1 is a thienotriazolodiazepine and a potent inhibitor of the BET family of bromodomain proteins which include BRD2, BRD3, BRD4, and the testis-specific protein BRDT in mammals. BET inhibitors structurally similar to JQ1 are being tested in clinical trials for a variety of cancers including NUT midline carcinoma. It was developed by the James Bradner laboratory at Brigham and Women's Hospital and named after chemist Jun Qi. The chemical structure was inspired by patent of similar BET inhibitors by Mitsubishi Tanabe Pharma. Structurally it is related to benzodiazepines. While widely used in laboratory applications, JQ1 is not itself being used in human clinical trials because it has a short half life.

Craig M. Crews is an American scientist at Yale University known for his contributions to chemical biology. He is known for his contributions to the field of induced proximity through his work in creating heterobifunctional molecules that "hijack" cellular processes by inducing the interaction of two proteins inside a living cell. His initial work focused on the discovery of PROteolysis-TArgeting Chimeras (PROTACs) to trigger degradation of disease-causing proteins, a process known as targeted protein degradation (TPD), and he has since developed new versions of -TACs to leverage other cellular processes and protein families to treat disease.

<span class="mw-page-title-main">Daniel Nomura</span> American chemical biologist

Daniel K. Nomura is an American chemical biologist and Professor of Chemical Biology and Molecular Therapeutics at the University of California, Berkeley, in the Departments of Chemistry and Molecular & Cell Biology. His work employs chemoproteomic approaches to develop small molecule therapeutics and therapeutic modalities against traditionally "undruggable" proteins.

Alessio Ciulli is an Italian British biochemist. Currently, he is the Professor of Chemical & Structural Biology at the School of Life Sciences, University of Dundee, where he founded and directs Dundee' new Centre for Targeted Protein Degradation (CeTPD). He is also the scientific co-founder and advisor of Amphista Therapeutics.

<span class="mw-page-title-main">Molecular glue</span> Class of chemical compounds

Molecular glue refers to a class of chemical compounds or molecules that play a crucial role in binding and stabilizing protein-protein interactions in biological systems. These molecules act as "glue" by enhancing the affinity between proteins, ultimately influencing various cellular processes. Molecular glue compounds have gained significant attention in the fields of drug discovery, chemical biology, and fundamental research due to their potential to modulate protein interactions, and thus, impact various cellular pathways. They have unlocked avenues in medicine previously thought to be "undruggable".

Chimeric small molecule therapeutics are a class of drugs designed with multiple active domains to operate outside of the typical protein inhibition model. While most small molecule drugs inhibit target proteins by binding their active site, chimerics form protein-protein ternary structures to induce degradation or, less frequently, other protein modifications.

Luxdegalutamide, also known as ARV-766, is an investigational oral androgen receptor (AR) degrader being developed by Arvinas for the treatment of metastatic castration-resistant prostate cancer (mCRPC). It belongs to a class of drugs called proteolysis targeting chimeras (PROTACs), which are designed to selectively degrade specific proteins by hijacking the ubiquitin-proteasome system. Luxdegalutamide is a second-generation PROTAC AR degrader that has demonstrated a broader efficacy profile and better tolerability compared to its predecessor, ARV-110, in clinical settings. It has shown promise in overcoming resistance associated with certain AR mutations, including the L702H mutation, which is prevalent in up to 24% of treated mCRPC patients. As of 2024, luxdegalutamide is being evaluated in phase I/II clinical trials for prostate cancer.

Gridegalutamide is an investigational oral androgen receptor (AR) degrader being developed for the treatment of metastatic castration-resistant prostate cancer (mCRPC). It belongs to a class of drugs called proteolysis targeting chimeras (PROTACs), which are designed to selectively degrade specific proteins by hijacking the ubiquitin-proteasome system. CC-94676 employs a unique dual mechanism of action, combining AR degradation with AR antagonism, potentially offering advantages over traditional AR inhibitors in overcoming resistance mechanisms. Initially developed by Celgene and now under Bristol Myers Squibb, CC-94676 has demonstrated AR protein degradation and suppression of tumor growth in CRPC mouse models. As of 2024, CC-94676 is being evaluated in phase I clinical trials for patients with mCRPC who have progressed on androgen-deprivation therapy and at least one prior secondary hormonal therapy.

References

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