Research progress on tamoxifen and its analogs associated with nuclear receptors.

Tamoxifen, a triphenylethylene-based selective estrogen-receptor modulator, is a landmark drug for the treatment of breast cancer and is also used for treating liver cancer and osteoporosis. Structural studies of tamoxifen have led to the synthesis of more than 20 novel tamoxifen analogs as receptor modulators, including 16 ERα modulators 2-17, an ERRß inverse agonist 19 and six ERRγ inverse agonists 20-25. This paper summarizes the research progress and structure-activity relationships of tamoxifen analogs modulating these three nuclear receptors reported in the literature, and introduces the relationship between these three nuclear receptor-mediated diseases and tamoxifen analogs to guide the research of novel tamoxifen analogs.

Research progress of anticancer drugs targeting CDK12.

Cyclin-dependent kinase 12 (CDK12) is a transcription-associated CDK that plays key roles in transcription, translation, mRNA splicing, the cell cycle, and DNA damage repair. Research has identified that high expression of CDK12 in organs such as the breast, stomach, and uterus can lead to HER2-positive breast cancer, gastric cancer and cervical cancer. Inhibiting high expression of CDK12 suppresses tumor growth and proliferation, suggesting that it is both a biomarker for cancer and a potential target for cancer therapy. CDK12 inhibitors can competitively bind the CDK12 hydrophobic pocket with ATP to avoid CDK12 phosphorylation, blocking subsequent signaling pathways. The development of CDK12 inhibitors is challenging due to the high homology of CDK12 with other CDKs. This review summarizes the research progress of CDK12 inhibitors, their mechanism of action and the structure-activity relationship, providing new insights into the design of CDK12 selective inhibitors.

Advances in Medicinal Chemistry of Estrogen-related Receptor Alpha (ERRα) Inverse Agonists.

Estrogen-related receptor alpha (ERRα), a member of the nuclear receptor superfamily, is strongly expressed in breast cancer cells. Its overexpression is associated with poor prognosis in triple- negative Breast Cancer (TNBC). ERRα expression could be inhibited by the downregulation of upstream oncogenic growth factors mTOR, HER2, and PI3K. Low expression of ERRα could suppress the migration and angiogenesis of tumor cells by inhibiting the activity of its downstream signals VEGF and WNT11. Studies have confirmed that ERRα inverse agonists can inhibit ERRα expression to treat breast cancer. Inverse agonists of ERRα could disrupt the interactions of ERRα with its coactivators and inhibit tumor development. Existing ERRα inverse agonists have shown moderate efficacy in inhibiting the growth of breast cancer cells. Clinical inverse agonists of ERRα have not been found in the literature. This review focuses on the research progress and the structureactivity relationship of ERRα inverse agonists, providing guidance for the research and discovery of new anti-tumor compounds for TNBC.

Research progress in Estrogen-related receptor gamma (ERRγ) agonists and inverse agonists.

Estrogen-related receptor gamma (ERRγ), one of three members of the ERR family, is an inducible transcription factor. ERRγ has dual functions in different tissues. The decreased expression of ERRγ in the brain, stomach, prostate, and fat cells can cause neuropsychological dysfunction, gastric cancer, prostate cancer, and obesity. However, when ERRγ is present in the liver, pancreas, and thyroid follicular cells, ERRγ overexpression is related to liver cancer, type II diabetes, oxidative liver injury, and anaplastic thyroid carcinoma. Signaling pathway studies have confirmed that ERRγ agonists or inverse agonists can regulate ERRγ expression to treat related diseases. The collision between residue Phe435 and the modulator is a key factor determining the activation or inhibition of ERRγ. Although more than 20 agonists and inverse agonists of ERRγ have been reported, no clinical studies have been found in the literature. This review summarizes the important relationship between ERRγ-related signaling pathways and diseases, research progress, and the structure-activity relationship of modulators. These findings provide guidance for further study on new ERRγ modulators.

A rapid approach to capture the potential bioactive compounds from Rhizoma Drynariae, utilizing disease-associated mutation in calcium sensing receptor to alter the binding affinity for agonists.

Rhizoma Drynariae (RD) was used clinically to treat osteoporosis in China due to stimulating bone formation and inhibiting bone resorption, however, the bioactive constituents with the dual effect on bone are still unknown exactly. Disease-causing mutations in calcium sensing receptor (CaSR) can alter parathyroid hormone secretion and affect Ca2+ release from bone and Ca2+ reabsorption from kidney, which gives an indication that CaSR is a potential target for developing therapeutics to manage osteoporosis. Herein, a chromatographic approach was established, by immobilizing the mutant CaSR onto the surface of silica gels as stationary phase in a one-step procedure and then adding the different amino acids into mobile phase as competitors, for exploring the binding features of the known agonists and further screening ligands from RD. The mutant CaSR-coated column was prepared rapidly without the complicated purification and separation of the receptor, which had the large capacity of 13.1 mg CaSR /g silica gels and kept a good stability and specificity for at least 35 days. The CaSR mutation can weaken the binding affinities for three agonists, and the largest decreases occurred on the mutational site Thr151Met for neomycin, on the two sites of Asn118Lys and Glu191Lys for gentamicin-C, and on the site Phe612Ser for kanamycin, which gained new insights into their structure-function relationship. The potential bioactive compounds from RD were screened using the mutant CaSR-coated column and were recognized as coumaric acid 4-O-ß-D-glucopyranoside, caffeic acid, and naringin using UPLC-MS. Among them, naringin targeting CaSR gives a possible explanation that RD could manage osteoporosis. These results indicated that, such a rapid and simple method, utilizing disease-associated mutation in CaSR to alter the binding affinity for agonists, can be applied in capturing the potential bioactive compounds efficiently from complex matrices like herb medicines.

The effect of pre-adsorption of OVA or WPC on subsequent OVA or WPC fouling on heated stainless steel surface.

Fouling on the heat exchanger surface during food processing has been researched extensively due to its great importance in energy efficiency, product quality and food safety. The nature of heat exchanger surface has an effect on the initial deposition behavior and deposit removal behavior to some degree. Protein adsorption on surface is considered to be the initial stage in fouling. In the current study, protein 'pre-adsorption' at room temperature on stainless steel has been investigated as a means to influence the behavior of protein fouling at pasteurization temperatures. Pre-adsorption was carried out with whey protein concentrate (WPC) and ovalbumin (OVA), respectively, which reduced the fouling of OVA (∼20-30% energy saving in the processing time examined). However, the pre-adsorption had little effect on fouling of whey protein concentrate. Contact angles were measured to show the surface change due to protein pre-adsorption. Protein pre-adsorption made the surfaces more hydrophilic.