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

作用方式

抑制剂

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

Welichem Biotech, Inc.

Ozmosis Research, Inc.

权益机构-

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-

登录后查看时间轴

结构/序列

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

登录后查看更多信息

100 项与 SLC-0111 相关的转化医学

登录后查看更多信息

100 项与 SLC-0111 相关的专利（医药）

登录后查看更多信息

124

项与 SLC-0111 相关的文献（医药）

2025-06-01·Bioorganic Chemistry

Development of novel amino-benzenesulfonamide derivatives and their analogues as carbonic anhydrase inhibitors: Design, synthesis, anticancer activity assessment, and pharmacokinetic studies using UPLC-MS/MS

Article

作者: Elsayad, Khaled A ; Mahmoud, Sally T ; Awadallah, Fadi M ; Giovannuzzi, Simone ; Supuran, Claudiu T ; Elmasry, Ghada F

The present study outlines the design and synthesis of dual-tail analogues of SLC-0111 as carbonic anhydrase inhibitors (CAIs) targeting tumor isoforms IX and XII 4a-h and 5a-h, along with pharmacokinetic studies. The synthesized compounds were evaluated for their inhibitory activity against four carbonic anhydrase isoforms (hCA I, II, IX, and XII), revealing potent activity, particularly against hCA IX and XII. Notably, compounds 4b, 5a, and 5b demonstrated strong inhibition of hCA IX with K_i values of 20.4, 12.9, and 18.2 nM, respectively, compared to acetazolamide (AAZ), which has a K_i of 25 nM. Additionally, compounds 5a, 5b, 5c, and 5d showed selective inhibition of hCA XII, with K_i values of 26.6, 8.7, 17.2, and 10.9 nM, respectively, relative to AAZ (K_i = 5.7 nM). Moreover, both series were tested for their anti-proliferative activity following the US-NCI protocol against a panel of more than fifty cancer cell lines. Compound 5h met the activity criteria and was automatically scheduled for further evaluation at five concentrations with 10-fold dilutions, revealing high toxicity toward leukemia and lower toxicity against melanoma. In addition, the MTT cytotoxicity assay was performed on 5f, 5d and acetazolamide using WI-38 cells. Furthermore, an in vivo pharmacokinetic study was conducted using UPLC-MS/MS on the most potent derivative, 5d, demonstrating a comparable pharmacokinetic profile compared to the reference drug acetazolamide. Furthermore, molecular docking prediction studies were conducted for the most active compounds, 5d and 5h, to elucidate their interactions with the active site hot spots of the CA isoform.

2025-03-01·Biochemical and Biophysical Research Communications

Molecular dynamics simulation reveals structural insights into isozyme selectivity of carbonic anhydrase XII inhibitors in hypoxic tumor microenvironment

Article

作者: Gao, Quan-Ze ; Saravanan, Venkatesan ; Kumaradoss, Kathiravan Muthu ; Palani, Sathiya Priya ; Valsaladevi, Anjana Gopi ; Chagaleti, Bharath Kumar

Human carbonic anhydrase (CA) isoenzymes IX and XII are overexpressed in cancer cells, contributing to tumor microenvironment acidification and representing important targets for cancer therapy. In this study, we identified compound V35 (ZINC09419065) as a selective inhibitor of CA IX and CA XII with enhanced binding stability and selectivity compared to standard inhibitors. We analyzed conserved regions in CA I, CA II, CA IX, and CA XII to investigate their isozyme selectivity, revealing critical selectivity determinants at positions 95, 141, and 203. Molecular docking results indicated that V35 interacts robustly with CA XII, forming a metal ion coordination complex with Zn via HIS94, HIS96, HIS119, and THR199, similar to the interaction pattern of standard inhibitor SLC-0111. Molecular dynamics (MD) simulations conducted over 500 ns under hypoxic conditions showed that V35 has high binding stability, with root mean square deviation (RMSD) and fluctuation (RMSF) values comparable to SLC-0111, demonstrating its conformational stability in CA XII. Binding free energy calculations using the MMGBSA method showed that V35 achieves binding free energy of -44.17 kcal/mol with CA XII, closely matching SLC-0111 (-49.41 kcal/mol). Density functional theory (DFT) calculations further highlighted V35's electrostatic potential distribution, supporting its isozyme selectivity. Post-dynamics analysis indicated that the ester functional groups and the inward movement of HIS64 stabilize V35's interactions in CA XII, a feature absent in CA I.

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.

100 项与 SLC-0111 相关的药物交易

登录后查看更多信息

研发状态

10 条进展最快的记录,

登录

后查看更多信息

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2期	加拿大	SignalChem Lifesciences Corp	2019-01-10
晚期恶性实体瘤	药物发现	加拿大	Welichem Biotech, Inc.	2014-10-01
晚期恶性实体瘤	药物发现	加拿大	Ozmosis Research, Inc.	2014-10-01

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

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	(觸構範網醖製鬱遞觸簾) = dosed at ≤1000 mg with fewer TRAE ≥ grade 3 and fewer AEs such as nausea and vomiting, compared with the 2000-mg cohort 簾壓簾夢顧鑰遞鹹餘鏇 (網鹹淵衊糧顧衊膚淵顧 ) 更多	积极	2020-07-01