SLC-0111(SLC-0111) - 药物靶点：CAIX_在研适应症：胰腺癌_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

CAIX

作用机制

CAIX抑制剂(碳酸酐酶IX抑制剂)

治疗领域

肿瘤消化系统疾病内分泌与代谢疾病

在研适应症

胰腺癌

非在研适应症

晚期恶性实体瘤转移性胰腺导管腺癌

原研机构

SignalChem Lifesciences Corp

在研机构

SignalChem Lifesciences Corp

非在研机构

Ozmosis Research, Inc.

Welichem Biotech, Inc.

最高研发阶段临床1/2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C13H12FN3O3S

InChIKeyYJQZNWPYLCNRLP-UHFFFAOYSA-N

CAS号178606-66-1

关联

2

项与 SLC-0111 相关的临床试验

NCT03450018 / Terminated临床1/2期IIT

An Open-label, Multi-center, Phase 1b Study to Investigate the Safety and Tolerability of SLC-0111 (WBI-5111) in Combination With Gemcitabine in Metastatic Pancreatic Ductal Adenocarcinoma Subjects Positive for Carbonic Anhydrase IX

This is a multi-center, open-label Phase 1b study of SLC-0111 (oral) in combination with IV gemcitabine in CA IX positive subjects with mPDAC and comprises of 2 parts:
Part 1: Dose Escalation
Part 2: Dose Expansion

开始日期2019-01-10

申办/合作机构

British Columbia Cancer Agency

[+2]

NCT02215850 / Completed临床1期

A Phase I, Multi-center, Open-label, Study to Investigate the Safety, Tolerability and Pharmacokinetic of SLC-0111 in Subjects With Advanced Solid Tumours

SLC-0111 is a selective, small molecule, inhibitor of carbonic anhydrase (CA) IX and is in development for the treatment of solid tumours over-expressing CA IX. CAIX, a transmembrane metalloenzyme, is overexpressed on extracellular surfaces of hypoxic tumour cells but its expression is highly restricted in normal tissue. CAIX is a functional regulator of processes critical for tumour growth and metastasis, including pH regulation, survival, migration and invasion.
This prospective single arm study will evaluate the safety of SLC-0111 given once daily in 28 day cycles in subjects with advanced solid tumours. The intent of this research study is to find our more information such as: the highest dose of SLC-0111 that can be given safely, the side effect it may cause, to examine how the body affects the study drug concentration in the blood (pharmacokinetics or PK), and to gain some information on its effectiveness in treating cancer.

开始日期2014-10-01

申办/合作机构

Welichem Biotech, Inc.

[+1]

100 项与 SLC-0111 相关的临床结果

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100 项与 SLC-0111 相关的转化医学

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100 项与 SLC-0111 相关的专利（医药）

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78

项与 SLC-0111 相关的文献（医药）

2024-12-01·Bioorganic Chemistry

Novel benzenesulfonamide derivatives as potential selective carbonic anhydrase IX, XII inhibitors with anti-proliferative activity: Design, synthesis and in silico studies

Article

作者: Mohamed, Fatma E A ; Nemr, Mohamed T.M. ; Nemr, Mohamed T M ; Sayed, Ahmed M. ; Khalil, Rehab G. ; Zidan, Taha H ; Fadaly, Wael A.A. ; Fadaly, Wael A A ; Mohamed, Fatma E.A. ; Zidan, Taha H. ; Sayed, Ahmed M ; Khalil, Rehab G

As inhibitors of carbonic anhydrases (CAs) IX and XII, a novel series of 1,2,3-triazole benzenesulfonamide derivatives 17a-l containing pyrazolyl-thiazole moiety was designed, synthesized, and tested for anti-proliferative activity. Compounds 17e-h demonstrated more effective inhibitory activity than acetazolamide (IC₅₀ 63 nM CA IX and IC₅₀ 92 nM CA XII), with IC₅₀ range of 25-52 nM against CA IX and IC₅₀ range of 31-80 nM against CA XII. To verify selectivity against CA IX and CA XII, carbonic anhydrase inhibitory activity of compounds 17e-h against the physiological CA I and CA II isoforms was carried out. The results showed that compounds 17e-h induced lower inhibitory activity against CA I and CA II with IC₅₀ range of 0.428-0.638 μM (CA I) and 0.095-0.164 μM (CA II), in addition to higher selectivity indices (CA I/CA IX S.I. 8.9-19.92, CA I/CA XII S.I. 5.78-16.06) and (CA II/CA IX S.I. 2.83-4.35, CA II/CA XII S.I. 2.05-3.15) when compared to that of acetazolamide, IC₅₀ of 0.199 μM (CA I), 0.133 μM (CA II) (CA I/CA IX S.I. 3.15, CA I/CA XII S.I. 2.16) and (CA II/CA IX S.I. 2.11, CA II/CA XII S.I. 1.44). Concerning anti-proliferative activity of compounds 17e-h, investigations were done on HEPG-2 cell line with IC₅₀ ranges of 3.44-15.03 μM in comparison, 5-FU and doxorubicin showed IC₅₀ values of 11.80 and 9.53 μM, respectively. Furthermore IC₅₀ of MCF-7 and MDA-MB-231 were determined under both normoxic and hypoxic conditions with IC₅₀ values ranging from 3.18-8.26 μM MCF-7 (normoxic), 1.39-6.05 μM MCF-7 (hypoxic), 7.13-26.3 μM MDA-MB-231 (normoxic), 0.76-16.3 μM MDA-MB-231 (hypoxic) using acetazolamide and SLC-0111 as selective CA inhibition references. Moreover, compounds 17e-h demonstrated greater safety against the normal cell line, MCF-10A, with IC₅₀ of 23.06-99.50 μM in comparison to 5-FU and doxorubicin IC₅₀ of 59.8 and 71.8 μM respectively. They also demonstrated (MCF-7 S.I. range of 3.77-31.28) in contrast to doxorubicin (S.I. 13.72) and (HepG-2 S.I. range of 3.60-6.95) in comparison to doxorubicin (S.I. 7.53). In relation to CA IX, XII inhibition, molecular docking of and ADME studies of sulfonamide derivatives 17a-l with CA IX (PDB: 5FL6) and CA XII (PDB: 1JD0) was carried out. Additionally, molecular dynamic simulation was carried out for compounds 17e and 17g which maintained good stability inside the active sites of both enzymes, with average RMSDs of 2.3 Å and 2.1 Å, respectively.

2024-10-24·Journal of Medicinal Chemistry

Benzoxaborinine, New Chemotype for Carbonic Anhydrase Inhibition: Ex Novo Synthesis, Crystallography, In Silico Studies, and Anti-Melanoma Cell Line Activity

Article

作者: Smietana, Michael ; Bonardi, Alessandro ; Massardi, Maria-Luisa ; Angeli, Andrea ; Ronca, Roberto ; Ferraroni, Marta ; Winum, Jean-Yves ; Supuran, Claudiu T. ; Nocentini, Alessio ; Turati, Marta ; Giovannuzzi, Simone ; Nikitjuka, Anna

The benzoxaborinine scaffold, a homologue of benzoxaborole with an additional carbon atom in the boracycle, shows significant potential in developing new therapeutic agents. This study reports the synthesis, inhibition assays against four human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, and anti-melanoma evaluation of 7-aryl(thio)ureido-substituted benzoxaborinines. Some derivatives, particularly compound 11, exhibited potent inhibitory activity (below 65 nM) against hCA IX and XII and stronger antiproliferative effects than SLC-0111 on human melanoma cells under hypoxia. Crystallographic studies of benzoxaborinine 3 adducts with hCA I and II demonstrated the binding mode of this chemotype, revealing that although both benzoxaborinine 3 and benzoxaborole 10 share a similar zinc-binding mode, the expanded ring in benzoxaborinine led to a different orientation within the active site. These findings suggest that benzoxaborinines hold promise for designing novel carbonic anhydrase inhibitors.

2024-10-01·Brain Tumor Pathology

Combination treatment with histone deacetylase and carbonic anhydrase 9 inhibitors shows therapeutic potential in experimental diffuse intrinsic pontine glioma

Article

作者: Fujita, Naohide ; Taccone, Michael S ; Sabha, Nesrin ; Arai, Hajime ; Siddaway, Robert ; Krumholtz, Stacey ; Smith, Christian ; Ishida, Joji ; McDonald, Paul ; Kondo, Akihide ; Dedhar, Shoukat ; Luck, Amanda ; Rutka, James ; Srikanthan, Dilakshan ; Levine, Adrian ; Bondoc, Andrew ; Hawkins, Cynthia ; Simoes, Sergio

Diffuse intrinsic pontine glioma (DIPG) remains a significant therapeutic challenge due to the lack of effective and safe treatment options. This study explores the potential of combining histone deacetylase (HDAC) and carbonic anhydrase 9 (CA9) inhibitors in treating DIPG. Analysis of RNA sequencing data and tumor tissue from patient samples for the expression of the carbonic anhydrase family and hypoxia signaling pathway activity revealed clinical relevance for targeting CA9 in DIPG. A synergy screen was conducted using CA9 inhibitor SLC-0111 and HDAC inhibitors panobinostat, vorinostat, entinostat, and pyroxamide. The combination of SLC-0111 and pyroxamide demonstrated the highest synergy and was selected for further analysis. Combining SLC-0111 and pyroxamide effectively inhibited DIPG cell proliferation, reduced cell migration and invasion potential, and enhanced histone acetylation, leading to decreased cell population in S Phase. Additionally, the combination therapy induced a greater reduction in intracellular pH than either agent alone. Data from this study suggest that the combination of SLC-0111 and pyroxamide holds promise for treating experimental DIPG, and further investigation of this combination therapy in preclinical models is warranted to evaluate its potential as a viable treatment for DIPG.

100 项与 SLC-0111 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
胰腺癌	临床2期	-	SignalChem Lifesciences Corp	2024-01-29
转移性胰腺导管腺癌	临床1期	加拿大	SignalChem Lifesciences Corp	2019-01-10
晚期恶性实体瘤	临床1期	加拿大	Welichem Biotech, Inc.	2014-10-01
晚期恶性实体瘤	临床1期	加拿大	Ozmosis Research, Inc.	2014-10-01

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02215850 (Pubmed \| Am J Clin Oncol) 人工标引	临床1期	HR阳性/HER2低表达实体瘤	-	SLC-0111	(夢構構願觸艱鏇憲願獵) = dosed at ≤1000 mg with fewer TRAE ≥ grade 3 and fewer AEs such as nausea and vomiting, compared with the 2000-mg cohort 製觸遞衊範範範觸選壓 (構製齋鏇艱窪範鑰醖選 ) 更多	积极	2020-07-01