共查询到7条相似文献,搜索用时 15 毫秒
1.
《药学学报(英文版)》2020,10(8):1476-1491
Ubiquitin specific peptidase 28 (USP28) is closely associated to the occurrence and development of various malignancies, and thus has been validated as a promising therapeutic target for cancer therapy. To date, only few USP28 inhibitors with moderate inhibitory activity have been reported, highly potent and selective USP28 inhibitors with new chemotypes remain to be discovered for pathologically investigating the roles of deubiquitinase. In this current study, we reported the synthesis and biological evaluation of new [1,2,3]triazolo[4,5-d]pyrimidine derivatives as potent USP28 inhibitors. Especially, compound 19 potently inhibited USP28 (IC50 = 1.10 ± 0.02 μmol/L, Kd = 40 nmol/L), showing selectivity over USP7 and LSD1 (IC50 > 100 μmol/L). Compound 19 was cellularly engaged to USP28 in gastric cancer cells. Compound 19 reversibly bound to USP28 and directly affected its protein levels, thus inhibiting the proliferation, cell cycle at S phase, and epithelial-mesenchymal transition (EMT) progression in gastric cancer cell lines. Docking studies were performed to rationalize the potency of compound 19. Collectively, compound 19 could serve as a new tool compound for the development of new USP28 inhibitors for exploring the roles of deubiquitinase in cancers. 相似文献
2.
Chung-Pu Wu Sung-Han Hsiao Hong-May Sim Shi-Yu Luo Wei-Cherng Tuo Hsing-Wen Cheng Yan-Qing Li Yang-Hui Huang Suresh V. Ambudkar 《Biochemical pharmacology》2013
The overexpression of the serine/threonine specific Polo-like kinase 1 (Plk1) has been detected in various types of cancer, and thus has fast become an attractive therapeutic target for cancer therapy. BI 2536 is the first selective inhibitor of Plk1 that inhibits cancer cell proliferation by promoting G2/M cell cycle arrest at nanomolar concentrations. Unfortunately, alike most chemotherapeutic agents, the development of acquired resistance to BI 2536 is prone to present a significant therapeutic challenge. One of the most common mechanisms for acquired resistance in cancer chemotherapy is associated with the overexpression of ATP-binding cassette (ABC) transporters ABCB1, ABCC1 and ABCG2. Here, we discovered that overexpressing of either ABCB1 or ABCG2 is a novel mechanism of acquired resistance to BI 2536 in human cancer cells. Moreover, BI 2536 stimulates the ATPase activity of both ABCB1 and ABCG2 in a concentration-dependent manner, and inhibits the drug substrate transport mediated by these transporters. More significantly, the reduced chemosensitivity and BI 2536-mediated G2/M cell cycle arrest in cancer cells overexpressing either ABCB1 or ABCG2 can be significantly restored in the presence of selective inhibitor or other chemotherapeutic agents that also interact with ABCB1 and ABCG2, such as tyrosine kinase inhibitors nilotinib and lapatinib. Taken together, our findings indicate that in order to circumvent ABCB1 or ABCG2-mediated acquired resistance to BI 2536, a combined regimen of BI 2536 and inhibitors or clinically active drugs that potently inhibit the function of ABC drug transporters, should be considered as a potential treatment strategy in the clinic. 相似文献
3.
Kim D Wang L Beconi M Eiermann GJ Fisher MH He H Hickey GJ Kowalchick JE Leiting B Lyons K Marsilio F McCann ME Patel RA Petrov A Scapin G Patel SB Roy RS Wu JK Wyvratt MJ Zhang BB Zhu L Thornberry NA Weber AE 《Journal of medicinal chemistry》2005,48(1):141-151
A novel series of beta-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (1) is a potent, orally active DPP-IV inhibitor (IC(50) = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclinical species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of compound 1, was selected for development as a potential new treatment for type 2 diabetes. 相似文献
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Pei Z Li X von Geldern TW Madar DJ Longenecker K Yong H Lubben TH Stewart KD Zinker BA Backes BJ Judd AS Mulhern M Ballaron SJ Stashko MA Mika AK Beno DW Reinhart GA Fryer RM Preusser LC Kempf-Grote AJ Sham HL Trevillyan JM 《Journal of medicinal chemistry》2006,49(22):6439-6442
Dipeptidyl peptidase IV (DPP4) deactivates glucose-regulating hormones such as GLP-1 and GIP, thus, DPP4 inhibition has become a useful therapy for type 2 diabetes. Optimization of the high-throughput screening lead 6 led to the discovery of 25 (ABT-341), a highly potent, selective, and orally bioavailable DPP4 inhibitor. When dosed orally, 25 dose-dependently reduced glucose excursion in ZDF rats. Amide 25 is safe in a battery of in vitro and in vivo tests and may represent a new therapeutic agent for the treatment of type 2 diabetes. 相似文献
6.
Folkes AJ Ahmadi K Alderton WK Alix S Baker SJ Box G Chuckowree IS Clarke PA Depledge P Eccles SA Friedman LS Hayes A Hancox TC Kugendradas A Lensun L Moore P Olivero AG Pang J Patel S Pergl-Wilson GH Raynaud FI Robson A Saghir N Salphati L Sohal S Ultsch MH Valenti M Wallweber HJ Wan NC Wiesmann C Workman P Zhyvoloup A Zvelebil MJ Shuttleworth SJ 《Journal of medicinal chemistry》2008,51(18):5522-5532
Phosphatidylinositol-3-kinase (PI3K) is an important target in cancer due to the deregulation of the PI3K/ Akt signaling pathway in a wide variety of tumors. A series of thieno[3,2-d]pyrimidine derivatives were prepared and evaluated as inhibitors of PI3 kinase p110alpha. The synthesis, biological activity, and further profiling of these compounds are described. This work resulted in the discovery of 17, GDC-0941, which is a potent, selective, orally bioavailable inhibitor of PI3K and is currently being evaluated in human clinical trials for the treatment of cancer. 相似文献
7.
Maaike E. Schutte Gerrit M. Alink Andreas P. Freidig Bert Spenkelink Judith C.H. Vaessen Johannes J.M. van de Sandt John P. Groten Ivonne M.C.M. Rietjens 《Food and chemical toxicology》2008
This study investigates whether the previous observation that quercetin increases the transport of PhIP through Caco-2 monolayers in vitro could be confirmed in an in vivo rat model. 相似文献