剂量递增阶段：主要目的：评估KY386在复发/难治性晚期恶性实体瘤患者中的安全性、耐受性和剂量限制性毒性。确定KY386治疗复发/难治性晚期恶性实体瘤患者的最大耐受剂量/最大给药剂量和扩展期推荐剂量。次要目的：评估KY386在复发/难治性晚期恶性实体瘤患者中的药代动力学特征。评估KY386在复发/难治性晚期恶性实体瘤患者中的初步抗肿瘤活性。剂量扩展阶段：主要目的：评估KY386在DHX33阳性的复发/难治性晚期恶性实体瘤患者中的安全性、耐受性和初步抗肿瘤活性。确定KY386在DHX33阳性的复发/难治性晚期恶性实体瘤患者中的II期临床研究推荐剂量。次要目的：评估KY386在DHX33阳性的复发/难治性晚期恶性实体瘤患者中的PK特征。探索性目的（适用于各阶段）：探索KY386的暴露量/剂量与安全性以及临床疗效之间的关系。探索KY386的药效动力学特征。

开始日期-

申办/合作机构

深圳开悦生命科技有限公司初创企业

100 项与 KY-386 相关的临床结果

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100 项与 KY-386 相关的转化医学

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100 项与 KY-386 相关的专利（医药）

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项与 KY-386 相关的文献（医药）

2024-10-02·Current Medicinal Chemistry

Design and Synthesis of Benzimidazole Carboxamide Cysteine Protease Inhibitors as Promising Anti-leishmanial Agents

Article

作者: Selvapandiyan, Angamuthu ; Tantray, Mushtaq A. ; Hamid, Hinna ; Beg, Mirza A. ; Kalicharan, Sharma ; Akhter, Gowsia ; Dhawan, Bharti ; Sayeed ur Rehman ; Alam, Mohammad Sarwar

Introduction:More than 20 protozoan species of Leishmania are responsible for causing Leishmaniasis, an infection spread by blood-feeding phlebotomine sandflies. A narrow pool of drugs is currently available rendering the current drug stratagem to treat this infection . Development of novel, less toxic, and more effective regimens is thus a need of the hour. Design and synthesis of benzo[d]imidazole carboxamides as agents to combat Leishmaniasis are also required.Methods:14 benzo[d]imidazole carboxamides were synthesized and gauged against L. donovani promastigotes and intramacrophage amastigote forms. All of the tested compounds exhibited significant anti-promastigote properties with IC50 well below 10 uM. Compounds 4a, 4b, and 4d, showing the highest anti-parasitic activity against promastigote forms (IC50 0.91- 1.33 μM), were also found to be associated with better anti-leishmanial potential (IC50 0.78- 1.67 μM) against the intramacrophage amastigotes comparable to Amphotericin-B (0.13 μM), a drug used for Leishmaniasis. Compound (4a), namely N-(2-(trifluoromethyl)-1Hbenzo[ d]imidazol-5-yl)benzo[d][1,3]-5-carboxamide-dioxole, was found to be most potent against L. donovani amastigotes among all the tested compounds, and demonstrated better antileishmanial properties (IC50 0.78 μM) when compared to the standard. Compound 4a was also assessed for its toxicity profile against THP-1 human monocytic cells. To establish the molecular target(s) in silico, molecular docking studies were performed against cysteine protease, a putative virulence factor of Leishmania parasites, and nucleoside diphosphate kinase, an enzyme with a critical role in nucleotide recycling, also associated with resistance in Leishmania strains. Compound 4a showed better binding affinity than the standard to these targets; furthermore, the molecular dynamic simulation studies further affirmed the stability of compound 4a, within the active site of the targets. In vitro, cysteine protease inhibitory activity (IC50 8.53 μM) using Bz-Arg-AMC hydrochloride fluorogenic peptide substrate established the promising potential of 4a as a cysteine protease inhibitor.Result:Computational ADMET analysis indicated appropriate pharmacokinetic profile and physicochemical characteristics for all members of the synthesized library.Conclusion:Both in vitro and in silico studies indicate that the synthesized imidazole carboxamides can act as potent hits and that N-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5- yl)benzo[d][1,3]-5-carboxamide-dioxole 4a can be an effective hit molecule which can be further developed into potent lead molecule (s) to fight Leishmania donovani.

2024-07-02·ACS Omega

An RNA Helicase DHX33 Inhibitor Shows Broad Anticancer Activity via Inducing Ferroptosis in Cancer Cells

Article

作者: Liang, Yingying ; Wen, Fuyu ; Deng, Yuanlian ; Zhang, Yandong ; Liao, Deqing ; Tang, Xiyu

RNA helicase DHX33 has been identified as a critical factor promoting cancer development. In the present study, a previously developed small molecule inhibitor for DHX33, KY386, was found to robustly kill cancer cells via a new path, the ferroptosis pathway. Mechanistically, DHX33 promotes the expression of critical players in lipid metabolism including FADS1, FADS2, and SCD1 genes, thereby sensitizing cancer cells to ferroptosis mediated cell death. Our study reveals a novel mechanism of DHX33 in promoting tumorigenesis and highlights that pharmacological targeting DHX33 can be a feasible option in human cancers. Normally differentiated cells are insensitive to DHX33 inhibition, and DHX33 inhibitors have little cellular toxicity in vitro and in vivo. Our studies demonstrated that DHX33 inhibitors can be promising anticancer agents with great potential for cancer treatment.

2020-08-31·Bioinformation

Molecular docking analysis of α2-containing GABAA receptors with benzimidazoles derivatives

Article

作者: Mzibri, Mohammed El ; Essassi, El Mokhtar ; Aliani, Aissam El ; Kasmi, Yassine ; Bouayyadi, Abdellatif ; Mesfioui, Abdelhalim ; Abbadi, Najia El ; Moussaif, Ahmed

It is of interest to study the binding capacity of "3-[2-(2-Amino-1H-benzo[d]imidazol-1-yl)ethyl]-1,3-oxazolidin-2-one" (OXB2) with the active site of gamma-aminobutyric acid (GABA) located in the GABA type A receptor (GABAAR) in comparison with different GABAA subtypes. Optimal binding features were observed with the α2β2γ2 isoform (-8 kcal/mol). This is similar (-7.3 and -7.2 kcal/mol, respectively) for subtypes (α3β2γ2 and α1β2γ2). This implies that OXB2 binds preferentially to subtypes associated with anxiety (α2- and/or α3-containing receptors) linked molecules than with the subtype associated with sedation (α1-containing receptors). It is further noted that molecular dynamics simulation data of the complex (OXB2-GABAAR) shows adequate structural stability in aqueous environment. Moreover, relevant ADMET data is found adequate for further consideration.

100 项与 KY-386 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
晚期恶性实体瘤	临床1期	中国	深圳开悦生命科技有限公司初创企业	2024-10-11
晚期癌症	临床申请批准	中国	深圳开悦生命科技有限公司初创企业	2024-06-12
胃癌	临床前	美国	深圳开悦生命科技有限公司初创企业	2024-09-24
肝细胞癌	临床前	美国	深圳开悦生命科技有限公司初创企业	2024-06-24