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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
An alternative strategy known as PROTAC (proteolysis targeting chimeras) has been developed and is also described below. PROTAC is based on the design of a bifunctional complex that utilizes the ubiquitin-protease system to selectively degrade the transcription factor of interest, thus inhibiting the transcription process. One advantage of this approach is that it does not require a high concentration of the bifunctional complex to produce a therapeutic effect. Thus, PROTAC has become a promising strategy for treating a number of diseases including cancer.
Protein Degradation Inducers SNIPERs and Protacs against Oncogenic Proteins
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Norihito Shibata, Nobumichi Ohoka, Takayuki Hattori, Mikihiko Naito
An alternative approach is downregulation of the target protein, which should have a potential therapeutic effect. Recently, we and others have developed a protein knockdown technology that induces degradation of target proteins using hybrid small molecules named SNIPERs [specific and non-genetic inhibitor of apoptosis protein (IAP)-dependent protein erasers] or PROTACs (proteolysis targeting chimeras). They are chimeric molecules consisting of two different ligands connected by a linker. One ligand is for the target protein, while the other is for E3 ubiquitin ligases. Accordingly, these molecules are expected to crosslink the target protein and E3 ubiquitin ligases in cells, resulting in ubiquitylation and subsequent degradation of the target protein via the ubiquitin-proteasome system (UPS) (Fig. 16.1). In this chapter, we present examples of drugs that act by degrading oncogenic proteins, and discuss the features and prospect of chemical degraders.
A patent review of selective CDK9 inhibitors in treating cancer
Published in Expert Opinion on Therapeutic Patents, 2023
Tizhi Wu, Xiaowei Wu, Yifan Xu, Rui Chen, Jubo Wang, Zhiyu Li, Jinlei Bian
Currently, safety is one of the biggest challenges in developing CDK9 inhibitors. To address this challenge, highly selective CDK9 inhibitors (>50-fold selectivity) have been intensively developed. However, high selectivity does not mean high safety. For example, the clinical study of selective CDK9 inhibitor 1 was terminated due to side effects. High selectivity is important for the study of biological mechanism of CDK9 in order to avoid off-target effects, but it is less important for clinical treatment efficacy. Therefore, CDK9 selectivity need not be overemphasized in relevant drug development. In addition, it is necessary to explore new technologies and strategies for targeting CDK9. Proteolysis targeting chimeras (PROTACs), a technology designed to induce the degradation of target proteins, have shown clear advantages, such as lower dosing and higher target specificity, and are being widely used in the development of various anti-tumor drugs [95]. CDK9 PROTACs may degrade CDK9 protein with greater selectivity and lower dosage, potentially reducing the side effects from CDK9 inhibitors. Additionally, the degradation of the CDK9-cyclinT complex has demonstrated potent anti-tumor activity [96], offering a new avenue for drug development targeting CDK9.
Ligands for cereblon: 2017–2021 patent overview
Published in Expert Opinion on Therapeutic Patents, 2022
Alexander Kazantsev, Mikhail Krasavin
The upsurge in the patenting activity related to CRBN ligands in the last 5 years is evidently linked by the advent of the proteolysis-targeting chimera (PROTAC) technology. Most of the new CRBN ligands are patented as ‘degrons,’ i. e. recruiters of CRBN as E3 ligase for targeted protein degradation. The new CRBN ligands have been invented by the five key players in the PROTAC field as Arvinas Operations, Inc. (the holder of PROTAC® registered trademark and originator of the technology), C4 Therapeutics, Inc., Dana-Farber Cancer Institute, Foghorn Therapeutics, Inc. and Kymera Therapeutics, Inc. The only company that develops CRBN ligands as new-generation IMiDs, not intended for use in the PROTAC construction is Celgene Corporation (now part of Bristol-Myers-Squibb) who did not actively patent their inventions and disclosed them in the general literature although their frontrunner candidate for multiple myeloma CC-92480 is currently in Phase I/II clinical study.
Quinacrine Depletes BCR-ABL and Suppresses Ph-Positive Leukemia Cells
Published in Cancer Investigation, 2019
Hu Lei, Yaoyao Tu, Li Yang, Jin Jin, Hao Luo, Hanzhang Xu, Jingwu Kang, Li Zhou, Yingli Wu
The chromosome translocation t(9;22) results in a BCR-ABL fusion gene, which encodes the BCR-ABL protein with constitutive tyrosine kinase activity (1). BCR-ABL fusion gene could be observed in both myeloid and lymphoblast leukemia cells (2). It is believed that the BCR-ABL positive leukemia occurs at the stem cell level (3). Tyrosine kinase inhibitors (TKIs) application has revolutionized the therapy of chronic myeloid leukemia (CML), but TKIs resistance and relapse are the current clinical problems. For example, TKIs, such as imatinib, inhibit the proliferation of leukemic cells by inhibiting the activity of the BCR-ABL protein. However, mutations at the binding site of BCR-ABL protein may lead to drug resistance, including T315I mutation (4). TKIs are highly effective in the chronic phase of the disease, but for the patient in the acute phase, the effect is very limited. Moreover, TKIs cannot eliminate the CML leukemia stem cells which are not dependent on BCR-ABL kinase activity for their survival (5). The degradation of BCR-ABL protein is believed to solve the problem of TKIs resistance. Oridonin and MK-8776 had been demonstrated to indirectly degrade the BCR-ABL protein by the ubiquitin proteasome pathway (6,7). Recently, Proteolysis Targeting Chimera (PROTAC) technology, which utilizes hetero-bifunctional small molecules whereby one end of the molecule recruits an E3 ubiquitin ligase while the other end engages the target protein, were demonstrated effectively degraded BCR-ABL protein (8). However, molecular drugs that effectively degrade BCR-ABL protein and eliminate leukemic stem cells are the best drug candidates.