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PROTAC-mediated Targeted Protein Degradation in Cancer: PARP, EGFR, and SMARCAs in Focus

Epigenetic Keys Unlock Secrets of the Heart

By Stuart P. Atkinson, Ph.D.

April 13, 2022


Are you a researcher hoping to target a disease-associated protein with small molecules, but have been left high and dry after finding out that it's considered "undruggable"? Fortunately, an exciting alternative route forward exists, with targeted protein degradation through proteolysis-targeting chimera (PROTAC) technology emerging as a therapeutically relevant approach in areas such as cancer (Békés, Langley, and Crews).

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Ubiquitination – Old News Becomes Good News

Ubiquitination is a well-known cellular process whereby proteins are “targeted” and thereby tagged for degradation in a dynamic, cell regulatory process. PROTAC molecules, which typically comprise a ligand for a targeted protein linked to an E3 ubiquitin ligase complex (Sakamoto et al.), repeatedly induce protein ubiquitination to capitalize on this mechanism to promote subsequent proteasomal degradation and reduce protein levels in a targeted manner. The first applications of targeted protein degradation by PROTAC molecules focused on cancer-associated proteins such as the estrogen (ER) and androgen (AR) receptors; now, we bring you two therapeutically relevant studies at the forefront of PROTAC research in this emerging field.

Our first study reports on the development of a novel PROTAC-mediated targeted protein degradation approach that targets the SMARCA2 SWI/SNF family chromatin remodeler as a safe, effective, and patient-compliant approach to cancer treatment (Kofink, Trainor, and Mair et al.). Meanwhile, our second study doubles down and describes a PROTAC molecule that simultaneously targets the degradation of two drug resistance-associated proteins (EGFR and PARP) as a highly synergistic means of inhibiting tumorigenesis or sensitizing tumors to other treatment strategies (Zheng et al.).

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PROTAC-mediated Targeted Degradation of a Chromatin Remodeler – An Effective & Patient-compliant Cancer Treatment?

Compared to intravenous or subcutaneous drug administration, the oral administration route for cancer targeting agents represents the optimal patient-compliant approach thanks to the general convenience and safety of this approach; however, this route presents significant obstacles to the translation of PROTAC molecules to the clinic due to their larger size and related physicochemical properties.

With this in mind, researchers led by Harald Weinstabl (Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria) and William Farnaby (University of Dundee, UK) sought to develop a new highly specific and orally available PROTAC molecule for the targeted protein degradation of the SMARCA2 protein (a SWI/SNF-family ATP-dependent chromatin remodeler). The authors initially sought to develop this approach to support an investigation into the synthetic lethality of SMARCA2-dependency in cancers deficient for SMARCA4, a closely related paralog.

As reported in their captivating ChemRxiv preprint, Kofink, Trainor, and Mair et al. applied structure- and property-guided rational design to the development of a SMARCA2-specific PROTAC molecule that employed the von Hippel-Lindau (VHL)/ElonginB-ElonginC (VCB) E3 ligase complex and optimized linking moieties, with the latter having significant influence the conformation of the entire PROTAC molecule. Encouragingly, this development strategy supported the synthesis of PROTAC molecules exhibiting elevated potency and pharmacokinetic properties suitable for oral administration.

Notably, a lead PROTAC molecule displayed high specificity for SMARCA2 when evaluated in ex vivo human whole blood assays and preferentially degraded SMARCA2 in vitro in a range of cancer cell lines; furthermore, the authors also described how the oral administration of their PROTAC molecule safely induced the near-complete degradation of SMARCA2 in vivo in mouse lung cancer xenograft models and prompted the inhibition of tumor growth.

Overall, the authors of this exciting study highlight their synthetic approach as a paradigm shift in the development of molecules appropriate for the oral administration route and underscore the successful therapeutic activity of their lead PROTAC molecule for the targeted and specific protein degradation of SMARCA2.

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Doubling-down! Novel Dual-targeted PROTAC Synergistically Attacks Drug Resistance in Cancer

But why target just one protein for PROTAC-mediated targeted degradation when we can double down and promote the degradation of a pair of disease-associated proteins as a potentially synergistic approach to cancer treatment? In their recent research, a team led by Lixia Chen (Shenyang Pharmaceutical University, Shenyang), Yirong Zhou, and Hua Li (Huazhong University of Science and Technology, Wuhan, China) took inspiration from successful clinical reports of small molecule-based combinatorial treatment regimens in cancer patients or dual-targeting drugs such as bispecific antibodies to develop PROTAC molecules with the ability to target two distinct proteins at the same time.

As reported in their fascinating Journal of Medicinal Chemistry study, Zheng et al. generated a library of rationally designed dual targeted PROTAC molecules using a highly efficient convergent synthetic strategy. Each PROTAC molecule employed trifunctional naturally occurring amino acids as star-shaped biocompatible linkers to connect two inhibitor molecules (which function as targeting agents for the proteins of interest) and an E3 ligand to simultaneously induce the targeted degradation of both target proteins.

As a proof-of-concept, the authors employed the epidermal growth factor receptor (EGFR) inhibitor gefitinib and the poly(ADP-ribose) polymerase (PARP) inhibitor Olaparib to develop a dual-targeted PROTAC molecule using different linker lengths that successfully induced the simultaneous degradation of EGFR and PARP protein in cancer cell lines thanks to the activity of the E3 ligand. In certain cancers, the overexpression of EGFR and PARP provides cancer cells with resistance to treatment approaches such as alkylating agents and ionizing radiation; therefore, inhibition of both EGFR and PARP may produce a synergistic effect with regards to tumor growth inhibition or therapeutic re-sensitization in cancers such as pancreatic and non-small cell lung cancer (Anighoro, Bajorath, and Rastelli).

The authors note the easy adaptation of their approach to the development of a broad range of dual-targeted PROTAC molecules, which they believe will significantly expand the application of PROTAC technology as a cancer treatment. Further noted combinations include pairs of synthetically lethal kinases, tumor immune targets combined with adjuvant immune targets, or epigenetic targets combined with antiapoptotic targets; however, issues concerning drug properties and pharmacokinetics arising from the increased molecular weight of dual-targeted PROTACs require attention before any potential in vivo evaluation.

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What's Next for Targeted Protein Degradation?

Overall, these studies of SMARCA2 and EGFR/PARP targeting as potential cancer treatments provide robust evidence for the therapeutic relevance of PROTAC-mediated targeted protein degradation – but what's next? In the field of epigenetics, PROTACs may provide for the highly specific degradation of histone/RNA/DNA-modifying enzymes; furthermore, dual-targeted PROTAC-mediated targeted protein degradation may also allow us to evaluate how various epigenetic modifications cooperate or antagonize each other in a straightforward manner.

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About the author

Stuart P. Atkinson

Stuart P. Atkinson, Ph.D.

Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!

Contact Stuart on Twitter with any questions

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