DNA-binding proteins, including transcription factors (TFs), play essential roles in various cellular processes and pathogenesis of diseases, deeming to be potential therapeutic targets. However, these proteins are generally considered undruggable as they lack an enzymatic catalytic site or a ligand-binding pocket. Proteolysis-targeting chimera (PROTAC) technology has been developed by engineering a bifunctional molecule chimera to bring a protein of interest (POI) to the proximity of an E3 ubiquitin ligase, thus inducing the ubiquitination of POI and further degradation through the proteasome pathway. Here, the development of oligonucleotide-based PROTAC (O'PROTACs), a class of noncanonical PROTACs in which a TF-recognizing double-stranded oligonucleotide is incorporated as a binding moiety of POI is reported. It is demonstrated that O'PROTACs of lymphoid enhancer-binding factor 1 (LEF1) and ETS-related gene (ERG), two highly cancer-related transcription factors, successfully promote degradation of these proteins, impede their transcriptional activity, and inhibit cancer cell growth in vitro and in vivo. The programmable nature of O'PROTACs indicates that this approach is also applicable to destruct other TFs. O'PROTACs not only can serve as a research tool but also can be harnessed as a therapeutic arsenal to target DNA binding proteins for effective treatment of diseases such as cancer.

The thia-Michael addition reactionh as been demonstrated to be ah ighly powerful tool in organic synthesis. Indeed, the influential natureo ft his reactionh as been wellestablished in the fields of medicinal chemistry,c atalysis, drug discovery,a nd materials science. The emergence of numerous synthetic strategies that take advantage of thia-Michael addition reactions of electron-deficienta lkenes has unleashed countless opportunities for the design and synthesis of diverse biologically relevant organosulfurc ompounds. However,d espite myriad potential synthetic applications, there has not been anye xclusive reviewso ft he thia-Michael addition reaction. Therefore, this Focus Review plots the journeyo ft he thia-Michael addition reaction in organic synthesis, and is categorized according to catalyzed and catalyst-free thia-Michael addition reactions. Figure 1. Summary of the applicationsoft hia-Michael adducts.[a] Dr.Scheme1.Catalyzed pathways for the thia-Michael addition reaction.EW-G = electron-withdrawing group.Scheme2.Acetic-acid-catalyzed thia-Michael additionr eaction proposed by Allen et al. [24] AsianJ.O rg.Scheme3.Indium-bromide-catalyzed thia-Michael addition reaction.Scheme4.Thia-Michael addition reaction followed by a1 ,2-addition of TMSCN in one pot. TMSCN = trimethylsilyl cyanide.Scheme5.Bi III -catalyzedt hia-Michael additionreactiono fa,b-unsaturated carbonyl compounds. Tf = trifluoromethanesulfonyl.Scheme6.Bismuth-triflate-catalyzed synthesis of bis-thioether compounds. Bn = benzyl.Scheme7.Iron-/copper-catalyzed thia-Michael additionr eaction.Scheme8.VO(OTf) 2 -mediated synthesis of b-mercapto ketones. Np = naphthyl.Scheme9.Substrate scope for the synthesis of 3-sulfanyl-substituted 1-(arylamino)-pyrrolidine-2,5-diones.Scheme10. Regio-and enantioselective addition at the d position of conjugated systems.Scheme11. Mechanistic modelf or the enantioselective d addition of at hiol to an a,b,g,d-unsaturated dienone,catalyzed by achiral Fe III Àsalenc omplex.Scheme12. Chemoselectivesynthesis of 2-amino-3,1-benzothiazines (15) and 3,4-dihydroquinazoline-2-thiones (16)byu sing ortho-aminocinnamate (13)a nd isothiocyanates 14.Scheme13. Reactionmechanism for the chemoselective synthesis of 2amino-3,1-benzothiazines (15)and 3,4-dihydroquinazoline-2-thiones (16).Scheme14. ZrCl 4 -assisted three-component reactionf or the synthesiso fbaryl-b-mercapto ketones.Scheme15. LiF-nanocube-mediated thia-Michael addition reaction.Scheme57. Ni II -catalyzed enantioselective synthesiso f2-aryl-3-nitrothiochroman-4-ols.Scheme58. Te ntative reaction mechanism for the Ni II -catalyzed asymmetric synthesis of 2-aryl-3-nitrothiochroman-4-ols.Scheme59. Pepsin-catalyzed synthesis of functionalized chiral dihydrothiophenes.Scheme69. Mechanistic aspects of the stereoselectives ynthesis of tetrahydrothioxanthenones.Scheme70. Enantioselectivesynthesis of methyl 2-((R)-2-nitro-1-(aryl/heteroaryl)ethylthio)acetatesa nd thiomorpholin-3-ones.Scheme71. Water-accelerated thia-Michael additionr eaction proposedb y Chakraborti and co-work...

Chirality is important in drug discovery because stereoselective drugs can ameliorate therapeutic difficulties including adverse toxicity and poor pharmacokinetic profiles. The human kinome, a major druggable enzyme class has been exploited to treat a wide range of diseases. However, many kinase inhibitors are planar and overlap in chemical space, which leads to selectivity and toxicity issues. By exploring chirality within the kinome, a new iteration of kinase inhibitors is being developed to better utilize the three-dimensional nature of the kinase active site. Exploration into novel chemical space, in turn, will also improve drug solubility and pharmacokinetic profiles. This perspective explores the role of chirality to improve kinome druggability and will serve as a resource for pioneering kinase inhibitor development to address current therapeutic needs.

In the past few years, breast cancer has become the most prevalent type of cancer. The majority of patients receive combinatorial chemotherapy treatments, which may result in increased risk of developing drug resistance, a reduced quality of life, and substantial side effects. Treatment modalities that could lessen the physical toll of standard treatments or act in synergy with chemotherapeutic treatments would benefit women worldwide. Research into tocotrienols has thus far demonstrated their potential to be such an agent, with tocotrienols surpassing the pharmacological potential of tocopherols. Further research using in vitro and preclinical breast cancer models to support clinical trials is needed. This review uses bibliometric analysis to highlight this gap in research and summarizes the current and future landscape of tocotrienols as an anti-breast cancer agent.

Multicomoponenet reactions (MCRs) are robust tools for the rapid synthesis of complex, small molecule libraries for use in drug discovery and development. By utilizing MCR chemistry, we developed a protocol to functionalize the C-3 position of imidazo[1,2-a]pyridine through a three component, decarboxylation reaction involving imidazo[1,2-a]pyridine, glyoxalic acid, and boronic acid.