류마티스관절염의 새로운 치료제인 소분자억제제

이은봉 ( Eun Bong Lee ) 대한류마티스학회 2012 대한류마티스학회지 Vol.19 No.3

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease predominantly affecting diarthroidal joints. Following the successful application of biologic agents, several small molecule inhibitors are currently under clinical trials. Small molecule inhibitors have several strengths compared with biologics. First, they can target several inflammatory cytokines together by blocking common signal transduction pathways. Second, they can be taken orally. Third, the price can be made flexible. Among the several small molecule inhibitors in the development process, fostamatinib and tofacitinib are the closest to the clinics at the moment. Fostamatinib, which is a Syk inhibitor, showed superior efficacy over placebo with tolerable safety signals. Diarrhea, hypertension and infection are representative adverse events. Tofacitinib, which is JAK inhibitor, is now finishing phase 3 clinical trials. It showed clinical efficacy comparable to Adalimumab and similar adverse effect profiles to the biologics, which include opportunistic infections. For laboratory abnormalities, leukopenia, anemia, increase of LDL and serum Cr were reported, which, however, were stabilized with prolonged use. Other classes of small molecule inhibitors did not show impressive efficacy as these small molecule inhibitors. In conclusion, small molecule inhibitors are promising novel therapeutic agents for the treatment of RA. They will be able to change the treatment paradigm of RA if they can show long-term safety.

Identification of a Lead small-molecule inhibitor of anthrax Lethal toxin by using fluorescence-based high-throughput screening

( Dong Wei ),( Zhao Yun Bu ),( Ai Lian Yu ),( Feng Li ) 생화학분자생물학회(구 한국생화학분자생물학회) 2011 BMB Reports Vol.44 No.12

Inhalational anthrax is caused by B. anthracis, a virulent spore- forming bacterium which secretes anthrax toxins consisting of protective antigen (PA), lethal factor (LF) and edema factor (EF). LF is a Zn-dependent metalloprotease and is the main determinant in the pathogenesis of anthrax. Here we report the identification of a lead small-molecule inhibitor of anthrax lethal factor by screening an available synthetic small-molecule inhibitor library using fluorescence-based high-throughput screening (HTS) approach. Seven small molecules were found to have inhibitory effect against LF activity, among which SM157 had the highest inhibitory activity. All theses small molecule inhibitors inhibited LF in a noncompetitive inhibition mode. SM157 and SM167 are from the same family, both having an identical group complex, which is predicted to insert into S1` pocket of LF. More potent small-molecule inhibitors could be developed by modifying SM157 based on this identical group complex. [BMB reports 2011; 44(12): 811-815]

건선에서 사용되는 소분자 억제제

변지연 대한건선학회 2018 대한건선학회지 Vol.15 No.2

Even though the recent advance in biologic therapy for psoriasis, there is still an unmet need for oral medications that can be administered long-term with favorable tolerability and safety. Small molecules modulate proinflammatory cytokines, selectively inhibit signaling pathways and show potential to treat inflammatory skin diseases. Presently, small molecules available for psoriasis are phosphodiesterase (PDE) 4 inhibitors and Janus Kinase (JAK) inhibitors. Apremilast, an oral PDE4 inhibitor, was approved by United States Food and Drug Administration in 2014 for psoriatic arthritis and psoriasis and also approved by Korea Food & Drug Administration in 2017. From several randomized controlled trials (RCTs), apremilast has demonstrated efficacy in patients with moderate to severe plaque psoriasis (28.8~39.8% of PASI75) at week 16. Most common adverse events of apremilast were diarrhea, nausea, and weight loss. Tofacitinib, a JAK1/3 inhibitor, was recently approved in several countries for the treatment of rheumatoid arthritis, but not for psoriasis. However, it is still under active investigation for psoriasis. From multiple global phase III RCTs, PASI 75 responses at week 12~24 were 33.5~46.0% with tofacitinib 5 mg bid and 55.2%~63.6% with 10 mg bid. Common adverse effects include nasopharyngitis, upper respiratory infection, and headache. Dose dependent laboratory abnormalities involving cytopenia, increased CPK and cholesterol and transaminitis can be observed. The clinical and safety evidence of PDE4 inhibitor, apremilast, and JAK inhibitors are reviewed here.

Small molecule inhibition of Epstein-Barr virus nuclear antigen-1 DNA binding activity interferes with replication and persistence of the viral genome

Lee, E.K.,Kim, S.Y.,Noh, K.W.,Joo, E.H.,Zhao, B.,Kieff, E.,Kang, M.S. Elsevier/North-Holland 2014 ANTIVIRAL RESEARCH Vol.104 No.-

The replication and persistence of extra chromosomal Epstein-Barr virus (EBV) episome in latently infected cells are primarily dependent on the binding of EBV-encoded nuclear antigen 1 (EBNA1) to the cognate EBV oriP element. In continuation of the previous study, herein we characterized EBNA1 small molecule inhibitors (H20, H31) and their underlying inhibitory mechanisms. In silico docking analyses predicted that H20 fits into a pocket in the EBNA1 DNA binding domain (DBD). However, H20 did not significantly affect EBNA1 binding to its cognate sequence. A limited structure-relationship study of H20 identified a hydrophobic compound H31, as an EBNA1 inhibitor. An in vitro EBNA1 EMSA and in vivo EGFP-EBNA1 confocal microscopy analysis showed that H31 inhibited EBNA1-dependent oriP sequence-specific DNA binding activity, but not sequence-nonspecific chromosomal association. Consistent with this, H31 repressed the EBNA1-dependent transcription, replication, and persistence of an EBV oriP plasmid. Furthermore, H31 induced progressive loss of EBV episome. In addition, H31 selectively retarded the growth of EBV-infected LCL or Burkitt's lymphoma cells. These data indicate that H31 inhibition of EBNA1-dependent DNA binding decreases transcription from and persistence of EBV episome in EBV-infected cells. These new compounds might be useful probes for dissecting EBNA1 functions in vitro and in vivo.

A novel small-molecule PPI inhibitor targeting integrin α_vβ₃-osteopontin interface blocks bone resorption in vitro and prevents bone loss in mice

Park, D.,Park, C.W.,Choi, Y.,Lin, J.,Seo, D.H.,Kim, H.S.,Lee, S.Y.,Kang, I.C. IPC Science and Technology Press 2016 Biomaterials Vol.98 No.-

<P>Small molecule-inhibition targeting protein-protein interaction (PPI) is now recognized as an emerging and challenging area in drug design. We developed a novel interactive drug discovery methodology known as Protein Chip technology (ProteoChip) as a cutting-edge PPI assay system applicable for unique PPI-targeting therapeutics integrated with computer-aided drug design (CADD). Here, we describe a novel small molecular PPI inhibitor, IPS-02001, which the blocks integrin alpha(v)beta(3)-osteopontin interface a novel PPI inhibitor identified by the interactive methodology of both ProteoChip- and CADD-based PPI assay. IPS-02001 (6,7-Dichloro-2,3,5,8-tetrahydroxy-1,4-naphthoquinone) was screened from different compound libraries (InterBioScreen, Commercial libraries) using an in silica structure-based molecular docking simulation method and a protein chip-based protein-protein interaction assay system. Additionally, integrin alpha(v)beta(3), an adhesion receptor expressed in osteoclasts (OCs), was implicated in the regulation of OC function via regulation of the cytoskeletal organization of OCs. IPS-02001 blocked OC maturation from murine bone marrow-derived macrophages, as well as the resorptive function of OCs. Moreover, treatment with IPS-02001 impaired downstream signaling of integrin alpha(v)beta(3) linked to Pyk2, c-Src, PLC gamma 2, and Vav3 and disrupted the actin cytoskeleton in mature OCs. Furthermore, IPS-02001 blocked RANKL-induced bone destruction by reducing the number of OCs and protected against ovariectomy-induced bone loss in mice. Thus, IPS-02001 may represent a promising new class of anti-resorptive drugs for treatment of bone diseases associated with increased OC function. (C) 2016 Elsevier Ltd. All rights reserved.</P>

Dual Inhibitors Against Topoisomerases and Histone Deacetylases

서영호 대한암예방학회 2015 Journal of cancer prevention Vol.20 No.2

Topoisomerases and histone deacetylases (HDACs) are considered asimportant therapeutic targets for a wide range of cancers, due to their association with the initiation, proliferation and survival of cancer cells. Topoisomerases are involved in the cleavage and religation processes of DNA, while HDACs regulate a dynamic epigenetic modification of the lysine amino acid on various proteins. Extensive studies have been undertaken to discover small molecule inhibitor of each protein and thereby, several drugs have been transpired from this effort and successfully approved for clinical use. However, the inherent heterogeneity and multiple genetic abnormalities of cancers challenge the clinical application of these single targeted drugs.In order to overcome the limitations of a single target approach, a novel approach, simultaneously targeting topoisomerases and HDACs with a single molecule has been recently employed and attracted much attention of medicinal chemists in drug discovery. This review highlights the current studies on the discovery of dual inhibitors against topoisomerases and HDACs, provides their pharmacological aspects and advantages, and discusses the challenges and promise of the dual inhibitors.

Subcellular Hsp70 Inhibitors Promote Cancer Cell Death via Different Mechanisms

Park, Sang-Hyun,Baek, Kyung-Hwa,Shin, Insu,Shin, Injae Elsevier 2018 Cell chemical biology Vol.25 No.10

<P><B>Summary</B></P> <P>Mechanisms underlying cancer cell death caused by inhibitors of subcellular Hsp70 proteins have been elucidated. An inhibitor of Hsp70, apoptozole (Az), is mainly translocated into lysosomes of cancer cells where it induces lysosomal membrane permeabilization, thereby promoting lysosome-mediated apoptosis. Additionally, Az impairs autophagy in cancer cells owing to its ability to disrupt the lysosomal function. However, the Az-triphenylphosphonium conjugate, Az-TPP-O3, localizes mainly to mitochondria of cancer cells where it inhibits the mortalin-p53 interaction and induces mitochondrial outer membrane permeabilization, consequently leading to mitochondria-mediated apoptosis. Unlike Az, Az-TPP-O3 does not have an effect on autophagy in cancer cells. Collectively, the findings indicate that inhibitors of lysosomal Hsp70 and mitochondrial mortalin enhance cancer cell death via distinctively different mechanisms. Additionally, the findings arising from this effort demonstrate that studies aimed at determining subcellular locations and functions of small-molecule modulators provide a deeper understanding of their modes of action in cells.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Inhibitors of different Hsp70 promote cancer cell death via different pathways </LI> <LI> An inhibitor of lysosomal Hsp70 induces LMP and promotes apoptosis </LI> <LI> An inhibitor of lysosomal Hsp70 impairs the autophagy process </LI> <LI> An inhibitor of mitochondrial mortalin induces MOMP and promotes apoptosis </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>

Glutaminase 저해 항암제 개발의 최근 발전 사항들

김규비(Gyubi Kim),주한솔(Hansol Joo),정종화(Jong-Wha Jung) 대한약학회 2021 약학회지 Vol.65 No.5

Glutaminolysis is closely related to uncontrolled tumor growth and metastasis in various glutamine-dependent cancers. As such, rewiring cancer metabolism using a glutaminolysis intervention has attracted much attention with recent progress in developing glutaminase inhibitors as anticancer agents. This review paper described the current understanding of glutaminases and their roles in cancers and small-molecule glutaminase inhibitors. In particular, recent developments of natural and synthetic glutaminase inhibitors were covered, focusing on their binding sites and isoform selectivity and briefly, on their structure-activity relationship. Some of the glutaminase inhibitors are in clinical trials, and if successful, it would lead to novel pharmacological intervention to effectively treat cancers.

FMS-like tyrosine kinase 3 inhibitors: a patent review

Lee, Jongkook,Paek, Seung-Mann,Han, Sun-Young Informa UK, Ltd. 2011 Expert opinion on therapeutic patents Vol.21 No.4

<P><B><I>Introduction:</I></B> Flt3 (FMS-like tyrosine kinase 3) has been presented as a target for novel anti-leukemic drugs because Flt3 mutations have been observed in acute myeloid leukemia (AML) cells. Due to both the poor efficacy and high toxicity of current standard AML therapies, there is an unmet need for new, improved therapies. Flt3 inhibitors have great potential to address this with mutated Flt3.</P><P><B><I>Areas covered:</I></B> This paper provides a comprehensive review of the Flt3 inhibitor patents currently available. Information from original research articles in peer-reviewed journals and current clinical developments from several resources is also described.</P><P><B><I>Expert opinion:</I></B> Our understanding of Flt3 inhibitors has been increased by findings from recent preclinical and clinical trials. Some Flt3 inhibitors show good efficacy in AML patients, but relapse and resistance to these inhibitors are still unavoidable. To address these problems, structurally diverse inhibitors, which exhibit inhibitory activities against both wild type and mutated Flt3, should be explored.</P>

Therapeutic strategies for metabolic diseases: Small-molecule diacylglycerol acyltransferase (DGAT) inhibitors.

Naik, Ravi,Obiang-Obounou, Brice W,Kim, Minkyoung,Choi, Yongseok,Lee, Hyun Sun,Lee, Kyeong Wiley-VCH 2014 CHEMMEDCHEM Vol.9 No.11

<P>Metabolic diseases such as atherogenic dyslipidemia, hepatic steatosis, obesity, and type II diabetes are emerging as major global health problems. Acyl-CoA:diacylglycerol acyltransferase (DGAT) is responsible for catalyzing the final reaction in the glycerol phosphate pathway of triglycerol synthesis. It has two isoforms, DGAT-1 and DGAT-2, which are widely expressed and present in white adipose tissue. DGAT-1 is most highly expressed in the small intestine, whereas DGAT-2 is primarily expressed in the liver. Therefore, the selective inhibition of DGAT-1 has become an attractive target with growing potential for the treatment of obesity and type II diabetes. Furthermore, DGAT-2 has been suggested as a new target for the treatment of DGAT-2-related liver diseases including hepatic steatosis, hepatic injury, and fibrosis. In view the discovery of drugs that target DGAT, herein we attempt to provide insight into the scope and further reasons for optimization of DGAT inhibitors.</P>