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BET Inhibitors as Anticancer Agents: A Patent Review
Ali, Imran,Choi, Gildon,Lee, Kwangho Bentham Science 2017 Recent patents on anti-cancer drug discovery Vol.12 No.4
<P>Background: Bromodomain and Extra Terminal (BET) family of bromodomain proteins (BRDs), comprised of four members in humans (BRD2, BRD3, BRD4, and BRDT), has emerged as a promising new cancer target class for small-molecule drug discovery.& para;& para;Objective: This review discusses the patent literature of BET inhibitors (2010-2017) for the treatment of cancer and other related diseases.& para;& para;Method: BET proteins act as 'epigenetic readers' and bind to acetylated lysine residues on the tails of histones H3 and H4. Inhibition of BET proteins for a wide array of therapeutic applications has led to the discovery and development of various BET inhibitors.& para;& para;Results: The increasing significance of BET inhibitors as a potential anticancer therapeutic has led to an extensive patent activity both from academia and pharmaceutical industry. Several of the BET inhibitors are under clinical development for the treatment of various kinds of cancers.& para;& para;Conclusion: The unmet needs and challenges associated with BET inhibition for cancer treatment have been portrayed in this review. An insight into the current developments and future prospects has been described as well.</P>
Contribution of a Low-Barrier Hydrogen Bond to Catalysis Is Not Significant in Ketosteroid Isomerase
Jang, Do Soo,Choi, Gildon,Cha, Hyung Jin,Shin, Sejeong,Hong, Bee Hak,Lee, Hyeong Ju,Lee, Hee Cheon,Choi, Kwan Yong Korean Society for Molecular and Cellular Biology 2015 Molecules and cells Vol.38 No.5
Low-barrier hydrogen bonds (LBHBs) have been proposed to have important influences on the enormous reaction rate increases achieved by many enzymes. ${\Delta}^5$-3-ketosteroi isomerase (KSI) catalyzes the allylic isomerization of ${\Delta}^5$-3-ketosteroid to its conjugated ${\Delta}^4$-isomers at a rate that approache the diffusion limit. Tyr14, a catalytic residue of KSI, has been hypothesized to form an LBHB with the oxyanion of a dienolate steroid intermediate generated during the catalysis. The unusual chemical shift of a proton at 16.8 ppm in the nuclear magnetic resonance spectrum has been attributed to an LBHB between Tyr14 $O{\eta}$ and C3-O of equilenin an intermediate analogue, in the active site of D38N KSI. This shift in the spectrum was not observed in Y30F/Y55F/D38N and Y30F/Y55F/Y115F/D38N mutant KSIs when each mutant was complexed with equilenin, suggesting that Tyr14 could not form LBHB with the intermediate analogue in these mutant KSIs. The crystal structure of Y30F/Y55F/Y115F/D38N-equilenin complex revealed that the distance between Tyr14 $O{\eta}$ and C3-O of the bound steroi was within a direct hydrogen bond. The conversion of LBHB to an ordinary hydrogen bond in the mutant KSI reduced the binding affinity for the steroid inhibitors by a factor of 8.1-11. In addition, the absence of LBHB reduced the catalytic activity by only a factor of 1.7-2. These results suggest that the amount of stabilization energy of the reaction intermediate provided by LBHB is small compared with that provided by an ordinary hydrogen bond in KSI.
Synthesis and Biological Evaluation of Tetrapeptide Ketones as Reversible 20S Proteasome Inhibitors
Latif, Muhammad,Jung, Myoung Eun,Lee, Kwangho,Choi, Gildon Korean Chemical Society 2014 Bulletin of the Korean Chemical Society Vol.35 No.12
Proteasome, a multicatalytic protease complex, has been validated as a promising therapeutic target in oncology. Carfilzomib (Kyprolis$^{(R)}$), a tetrapeptide epoxyketone, irreversibly inhibits the chymotrypsin-like (CT-L) activity of the proteasome and has been recently approved for multiple myeloma treatment by FDA. A chemistry effort was initiated to discover the compounds that are reversibly inhibit the proteasome by replacing the epoxyketone moiety of carfilzomib with a variety of ketones as reversible and covalent warheads at the C-terminus. The newly synthesized compounds exhibited significant inhibitory activity against CT-L activity of the human 20S proteasome. When the compounds were tested for cancer cell viability, 14-8 was found to be most potent in inhibiting Molt-4 acute lymphoblastic leukemia cell line with a $GI_{50}$ of $4.4{\mu}M$. Cytotoxic effects of 14-8 were further evaluated by cell cycle analysis and Western blotting, demonstrating activation of apoptotic pathways.
Eom, Min Sik,Jang, Woojeong,Lee, Yoon Seo,Choi, Gildon,Kwon, Yong-Uk,Han, Min Su The Royal Society of Chemistry 2012 Chemical communications Vol.48 No.45
<P>In this study, the use of bi-ligand co-functionalized gold nanoparticles in a highly selective and sensitive colorimetric probe for Ca<SUP>2+</SUP> ions is demonstrated and this probe also determined the concentrations of Ca<SUP>2+</SUP> ions in serum samples.</P> <P>Graphic Abstract</P><P>The use of bi-ligand co-functionalized gold nanoparticles in a highly selective and sensitive colorimetric probe for Ca<SUP>2+</SUP> ions is demonstrated and this probe also determined the concentrations of Ca<SUP>2+</SUP> ions in serum samples. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=c2cc31724a'> </P>
Identification of TRD-35 as Potent and Selective DRAK2 Inhibitor
Imran Ali,Sangjun Park,정명은,Nari Lee,Maimoona Bibi,채종학,양경민,김성진,Gildon Choi,이광호 대한화학회 2020 Bulletin of the Korean Chemical Society Vol.41 No.5
Proposed binding mode of TRD-35 (thick cyan sticks) in the DRAK2.
Discovery of TRD-93 as a novel DRAK2 inhibitor
Sangjun Park,Seungmin Kye,Myoung Eun Jung,Chong Hak Chae,Kyung-Min Yang,Seong-Jin Kim,Gildon Choi,Kwangho Lee 대한화학회 2023 Bulletin of the Korean Chemical Society Vol.44 No.5
Death-associated protein kinase-related apoptosis-inducing protein kinase 2 (DRAK2) has become a promising target for drug development. In search of novel and selective DRAK2 inhibitor motif, in vitro screen kinase assay was established performed using in-house chemical libraries. After through hit triage procedure, N2-(3,5-dichlorophenyl)-5-fluoro-N4-methylpyrimidine-2,4-diamine (1) was selected as initial hit with structural novelty and drug-likeness. During hit validation, structure–activity relationship of 1 was thoroughly disclosed and TRD- 93 was finally validated as hit for DRAK2 inhibition. TRD-93 is small (mw = 290) but selectively potent to DRAK2 (IC50 = 0.16 μM) over other kinases including DAPK family kinases. Molecular binding model study of TRD-93 to DRAK2 is also discussed.