TaeHun Kim

Discovery and development of heat shock protein 90 inhibitors as anticancer agents: a review of patented potent geldanamycin derivatives

Introduction: There has been research on anticancer strategies which focus on disrupting a single malignant protein. One of the strategies is the inhibition of one protein, heat shock protein 90 (Hsp90). There are many reasons why Hsp90 protein is targeted by anticancer agents: maintenance of cellular homeostasis in organisms involves Hsp90 and its client proteins; moreover, Hsp90 complex is involved in regulating several signal transduction pathways and plays an important role in the maturation of lots of tumor-promoting client proteins. Geldanamycin (GM), the first benzoquinone ansamycin, has shown anticancer activity by binding to Hsp90. Currently, several GM derivatives such as 17-AAG, 17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin, IPI-493, and IPI-504 are being progressively developed toward clinical application. Areas covered: Several research groups have studied GM and its derivatives to develop novel and potent Hsp90 inhibitors for the treatment of cancer. The crystal structure of Hsp90 was utilized to undergo structural optimization of GM derivatives. A wide variety of structural modifications were performed and some of the derivatives are now in clinical studies. The aim of this review was to summarize and analyze the structure-activity relationships of GM derivatives and the focus is on patented novel and pharmaceutically efficacious derivatives published from 1971 to 2012. Expert opinion: Hsp90 inhibitors offer an effective therapeutic approach for treatment of cancer. To date, the clinical results of 17-AAG, IPI-493, and IPI-504 suggest that these GM derivatives could be used either alone or in combination with other marketed medications for the treatment of cancer patients. As there are not any marketed Hsp90 inhibitors, inhibiting Hsp90 chaperone function remains as a promising strategy that still requires further research.

Discovery and biological evaluation of tetrahydrothieno[2,3-c]pyridine derivatives as selective metabotropic glutamate receptor 1 antagonists for the potential treatment of neuropathic pain

Metabotropic glutamate receptor 1 (mGluR1) has been a prime target for drug discovery due to its heavy involvement in various brain disorders. Recent studies suggested that mGluR1 is associated with chronic pain and can serve as a promising target for the treatment of neuropathic pain. In an effort to develop a novel mGluR1 antagonist, we designed and synthesized a library of compounds with tetrahydrothieno[2,3-c]pyridine scaffold. Among these compounds, compound 9b and 10b showed excellent antagonistic activity inxa0vitro and demonstrated pain-suppressing activity in animal models of pain. Both compounds were orally active, and compound 9b exhibited a favorable pharmacokinetic profile in rats. We believe that these compounds can provide a promising lead compound that is suitable for the potential treatment of neuropathic pain.

Discovery of benzimidazole derivatives as modulators of mitochondrial function: A potential treatment for Alzheimer's disease.

In this study, we designed a library of compounds based on the structures of well-known ligands of the 18xa0kDa translocator protein (TSPO), one of the putative components of the mPTP. We performed diverse mitochondrial functional assays to assess their ability to restore cells from Aβ-induced toxicity inxa0vitro and inxa0vivo. Among tested compounds, compound 25 effectively improved cognitive function in animal models of AD. Given the excellent inxa0vitro and inxa0vivo activity and a favorable pharmacokinetic profile of compound 25, we believe that it can serve as a promising lead compound for a potential treatment option for AD.

Synthesis and biological evaluation of aryl isoxazole derivatives as metabotropic glutamate receptor 1 antagonists: a potential treatment for neuropathic pain.

Glutamate is the major excitatory neurotransmitter and known to activate the metabotropic and ionotropic glutamate receptors in the brain. Among these glutamate receptors, metabotropic glutamate receptor 1 (mGluR1) has been implicated in various brain disorders including anxiety, schizophrenia and chronic pain. Several studies demonstrated that the blockade of mGluR1 signaling reduced pain responses in animal models, suggesting that mGluR1 is a promising target for the treatment of neuropathic pain. In this study, we have developed mGluR1 antagonists with an aryl isoxazole scaffold, and identify several compounds that are orally active in vivo. We believe that these compounds can serve as a useful tool for the investigation of the role of mGluR1 and a promising lead for the potential treatment of neuropathic pain.

Discovery of 2-aryloxy-4-amino-quinazoline derivatives as novel protease-activated receptor 2 (PAR2) antagonists

Protease-activated receptor 2 (PAR2) is a member of G protein-coupled receptor and its activation initiates diverse inflammatory responses. Recent studies suggest that antagonists of PAR2 may provide a novel therapeutic strategy for inflammatory diseases. In this study, we have developed a series of 2-aryloxy-4-amino-quinazoline derivatives as PAR2 antagonists and examined their effects against LPS-induced inflammatory responses in RAW 264.7 macrophages. Among these derivatives, compound 2f displayed the greatest antagonistic activity with the IC50 value of 2.8μM. Binding modes of the newly identified PAR2 antagonists were analyzed by molecular docking using IFD/MM-GBSA methods in the putative binding site of PAR2 homology model. Moreover, 2f demonstrated significant inhibitory effects on the LPS-activated pro-inflammatory mediators including nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) through the regulation of various intracellular signaling pathways involving nuclear factor-κB (NF-κB), activator protein 1 (AP-1) and the mitogen-activated protein kinases (MAPK). Furthermore, administration of 2f significantly reduced the mortality of LPS-induced sepsis in mice. These results provide useful insights into the development of novel PAR2 antagonists with anti-inflammatory activity in vitro and in vivo.

In silico probing and biological evaluation of SETDB1/ESET-targeted novel compounds that reduce tri-methylated histone H3K9 (H3K9me3) level

ERG-associated protein with the SET domain (ESET/SET domain bifurcated 1/SETDB1/KMT1E) is a histone lysine methyltransferase (HKMT) and it preferentially tri-methylates lysine 9 of histone H3 (H3K9me3). SETDB1/ESET leads to heterochromatin condensation and epigenetic gene silencing. These functional changes are reported to correlate with Huntington’s disease (HD) progression and mood-related disorders which make SETDB1/ESET a viable drug target. In this context, the present investigation was performed to identify novel peptide-competitive small molecule inhibitors of the SETDB1/ESET by a combined in silico–in vitro approach. A ligand-based pharmacophore model was built and employed for the virtual screening of ChemDiv and Asinex database. Also, a human SETDB1/ESET homology model was constructed to supplement the data further. Biological evaluation of the selected 21 candidates singled out 5 compounds exhibiting a notable reduction of the H3K9me3 level via inhibitory potential of SETDB1/ESET activity in SETDB1/ESET-inducible cell line and HD striatal cells. Later on, we identified two compounds as final hits that appear to have neuronal effects without cytotoxicity based on the result from MTT assay. These compounds hold the calibre to become the future lead compounds and can provide structural insights into more SETDB1/ESET-focused drug discovery research. Moreover, these SETDB1/ESET inhibitors may be applicable for the preclinical study to ameliorate neurodegenerative disorders via epigenetic regulation.Graphical Abstract

Discovery of thienopyrrolotriazine derivatives to protect mitochondrial function against Aβ-induced neurotoxicity

Recovery of mitochondrial dysfunction has gained increasing attention as an alternative therapeutic strategy for Alzheimers disease (AD). Recent studies suggested that the 18xa0kDa mitochondrial translocator protein (TSPO) has the potential to serve as a drug target for the treatment of AD. In this study, we generated a structure-based pharmacophore model and virtually screened a commercial library, identifying SVH07 as a virtual hit, which contained a tricyclic core structure, thieno[2,3:4,5]pyrrolo[1,2-d][1,2,4]triazine group. A series of SVH07 analogues were synthesized and their effects on the mitochondrial membrane potential and ATP production were determined by using neuronal cells under Aβ-induced toxicity. Among these analogues, compound 26 significantly recovered mitochondrial membrane depolarization and ATP production. Inxa0vitro binding assays indicated that SVH07 and 26 showed high affinities to TSPO with the IC50 values in a nanomolar range. We believe that compound 26 is a promising lead compound for the development of TSPO-targeted mitochondrial functional modulators with therapeutic potential in AD.

In silico‐designed novel non‐peptidic ABAD LD hot spot mimetics reverse Aβ‐induced mitochondrial impairments in vitro

Present work aimed to introduce non‐peptidic ABAD loop D (LD) hot spot mimetics as ABAD‐Aβ inhibitors. A full‐length atomistic model of ABAD‐Aβ complex was built as a scaffold to launch the lead design and its topology later verified by cross‐checking the computational mutagenesis results with that of in vitro data. Thereafter, the interactions of prime Aβ‐binding LD residues—Tyr101, Thr108, and Thr110—were translated into specific pharmacophore features and this hypothesis subsequently used as a virtual screen query. ELISA‐based screening of 20 hits identified two promising lead candidates, VC15 and VC19 with an IC50 of 4.4 ± 0.3 and 9.6 ± 0.1 μm, respectively. They productively reversed Aβ‐induced mitochondrial dysfunctions such as mitochondrial membrane potential loss (JC‐1 assay), toxicity (MTT assay), and ATP reduction (ATP assay) in addition to increased cell viabilities. This is the first reporting of LD hot spot‐centric in silico scheme to discover novel compounds with promising ABAD‐Aβ inhibitory potential. These chemotypes are proposed for further structural optimization to derive novel Alzheimers disease (AD) therapeutics.