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Protein Degradation Inducers SNIPERs and Protacs against Oncogenic Proteins
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Norihito Shibata, Nobumichi Ohoka, Takayuki Hattori, Mikihiko Naito
To improve the protein knockdown activity of PRORACs, Dr. Crews’ group developed hydroxyproline-based small molecules targeting VHL (Buckley et al., 2012a; Buckley et al., 2012b; Galdeano et al., 2014; Frost et al., 2016). They synthesized all small molecule PROTACs consisting of VHL032 (a VHL ligand) and a ligand of estrogen-related receptor a (ERRα) or receptor-interacting serine-threonine kinase 2 (RIPK2) (Bondeson et al., 2015). These novel VHL-recruiting PROTACs induce significant degradation of ERRα and RIPK2 at 100 and 3 nM, respectively. In addition, the VHL-recruiting PROTAC against ERRα provides broad tissue distribution and knockdown of ERRα protein in a tumor xenograft model. Using the VHL ligand or its derivative, potent PROTACs were also developed against oncogenic proteins such as BRD4 (Raina et al., 2016), TRIM24 (Gechijian et al., 2018), and receptor tyrosine kinases (epidermal growth factor receptor, HER2, and c-MET) (Burslem et al., 2018).
Endocrine and Metabolic Side Effects
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
Ayse Serap Karadag, Emin Ozlu, Bodo C. Melnik
The physiologic effects of retinoids are regulated by retinoic acid receptors (RAR-α, -β, and -γ isoforms) and retinoid X receptor (RXR-α, -β, and -γ isoforms) (21) (Table 17.1). RAR and RXR are members of a broad family of nuclear receptors including steroid, thyroid hormone, vitamin D, liver X receptor (LXR), and peroxisome proliferator-activated receptors (PPARs). They act as ligand-dependent transcription factors. Many tissues are targeted by retinoids through different heterodimeric complexes (3). Importantly, retinoids have also a significant impact on stem cell differentiation (22). ATRA induces differentiation primarily by binding to RARs, which are the transcription factors that associate with RXRs and bind retinoic acid response elements (RAREs) in the nucleus. Binding of ATRA (22): Initiates changes in interactions of RAR/RXRs with co-repressor and co-activator proteins, activating transcription of primary target genes.Alters interactions with proteins that induce epigenetic changes.Induces transcription of genes encoding transcription factors and signaling proteins that further modify gene expression and induce a secondary gene response (e.g., upregulation of p53, FoxO1, FoxO3, TRAIL) and results in alterations in estrogen receptor α signaling (3,20). Proteins that bind at or near RAREs include Sin3a, N-CoR1, PRAME, Trim24, NRIP1, Ajuba, Zfp423, and MN1/TEL. Interactions among retinoids, RARs/RXRs, and these proteins explain in part the powerful effects of retinoids on stem cell differentiation.
High Expression of TRIM15 Is Associated with Tumor Invasion and Predicts Poor Prognosis in Patients with Gastric Cancer
Published in Journal of Investigative Surgery, 2021
Weiran Zhou, Hao Chen, Yuanyuan Ruan, Xiaoqing Zeng, Fenglin Liu
Tripartite motif (TRIM) family proteins belong to a large conserved family and there are over 70 members. Several reviews described that TRIM proteins are implicated in plenty of cellular activities such as transcription, autophagy, carcinogenesis and so on [4–7]. The tripartite motif structure is consisted of a RING-finger domain, one or two B-box finger domains and a coiled-coil domain [8]. Because of the RING-finger domain, most of the TRIM proteins are characterized as E3 ubiquitin ligases [9]. Much of the research in the last decade has revealed that quite a lot of TRIM proteins are related to the malignancy of cancers including TRIM24, TRIM28 and TRIM29 [10–12]. It has been found that the expression of TRIM proteins was altered in prostate cancer, breast cancer and lung cancer [13–15].
The therapeutic potential of PROTACs
Published in Expert Opinion on Therapeutic Patents, 2021
Andrew B. Benowitz, Katherine L. Jones, John D. Harling
The earliest PCT patent filing exemplifying non-BET bromodomain PROTACs was published in 2017 by the Dana-Farber Cancer Institute [141]. This filing exemplified PROTAC degraders of TRIM24, which is a protein that has been reported to possess epigenetic reader functionality in addition to other functions, and which has been correlated with multiple cancer types when aberrantly overexpressed [142]. Compounds exemplified in this filing used both cereblon and VHL binders as the E3 ligase-recruiting element, and employed modified versions of the previously reported dual TRIM24-BRPF1 bromodomain inhibitor IACS-9571 [143] as the TRIM24 targeting ligand. No discrete DC50 or Dmax degradation data were reported for any exemplified compound in this filing, but several compounds (e.g. compound 63, Figure 15) were described as causing significant TRIM24 protein loss in 293 T cells after 18 h.
TRIM13 inhibits cell migration and invasion in clear-cell renal cell carcinoma
Published in Nutrition and Cancer, 2020
Hualei Li, Lili Qu, Rui Zhou, You Wu, Shujun Zhou, Yueping Zhang, Bing Cheng, Jian Ni, Hua Huang, Jianquan Hou
The tripartite motif (TRIM)-containing proteins have many functions in different biological processes, so it has attracted enough attention (6, 7). TRIM13, a member of the TRIM family, is a RING domain containing E3 ubiquitin ligase which plays critical roles in diverse cellular processes including cell death, cancer and antiviral immunity. Recent studies have shown that some tripartite motif (TRIM) protein members, characterized by a conservative RING finger, B-box, and coiled-coil domains, can act as important regulators of carcinogenesis (7). While TRIM13 has little knowledge of the biological characteristics of human cancer, many family members have investigated and are related to cell growth and development (8). TRIM29 expression can be a good marker for lymph node metastasis in gastric cancer (9). TRIM44 has important carcinogenic effects and is a potential therapeutic target for gastric cancer (10). In addition, it is reported that TRIM24 is crucial for the development of hepatocellular carcinoma, regulating the apoptosis, cell cycle and EMT of hepatocellular carcinoma cells (11). As far as we know, the possible correlation between TRIM13 expression and the clinicopathological factors of human Clear cell renal cell carcinoma has not been reported.