SLC-0111 / SignalChem Lifesci, Welichem - LARVOL DELTA

Tailored mechano-responsive micelles mimic the iron starvation response and impair pH homeostasis for triggered cancer therapy. (PubMed, J Control Release) - "To address this issue, we report a mechano-responsive ferrocene-bearing micelle that mimics the CAIX/NFS1 axis via ultrasound-activated iron release and the co-delivery of SLC-0111, a CAIX inhibitor...The in vivo efficacy studies in a 4 T1 breast cancer model confirmed potent tumor suppression with minimal systemic toxicity. This work introduces a mechanical force-controlled strategy as a substitute for CAIX/NFS1 synthetic lethality therapy without the interference of oxygen level, holding promise for advancing tumor-specific therapy."

Journal • Breast Cancer • Oncology • Solid Tumor • CA9

Green Synthesis of Sulfonamide Derivatives as Human Carbonic Anhydrase Isoforms I, II, IX, XII Inhibitors and Antioxidants: Comprehensive Insights From Biological Evaluation and In-Depth In Silico Analysis. (PubMed, J Biochem Mol Toxicol) - "These sulfonamides exhibited significant inhibition compared to standard carbonic anhydrase inhibitors such as acetazolamide, ethoxzolamide, zonisamide, methazolamide, dorzolamide, and SLC-0111. ADMET predictions indicated favorable physicochemical properties and compliance with Lipinski's rule. These results highlight the potential of these aromatic sulfonamide derivatives as potent inhibitors of human carbonic anhydrase isoforms, with promising antioxidant activity, suggesting their potential therapeutic applications in conditions such as retinal and cerebral edema, glaucoma, epilepsy, high-altitude sickness, and cancer."

Journal • CNS Disorders • Epilepsy • Glaucoma • Oncology • Ophthalmology

An ureido-substituted benzenesulfonamide carbonic anhydrase inhibitor exerts a potent antitumor effect in vitro and in vivo. (PubMed, Exp Hematol Oncol) - "To date, several CA IX targeting approaches have been developed to inhibit its activity in neoplastic tissues including the clinical grade (Phase Ib/II) ureido-substituted benzenesulfonamide SLC-0111, which has been widely investigated over the past years...Finally, we evaluated the safety profile of FC-531 in vivo and demonstrated its capacity to reduce tumor growth and metastatization in vivo. Together, our data provide the rationale for the exploitation of FC-531 as a potent CA IX inhibitor for the management of different CA IX- expressing solid tumors."

Journal • Preclinical • Oncology • Solid Tumor • CA9

Discovery of novel thiourea benzenesulfonamides based 1,8-naphthalimide derivatives as carbonic anhydrase IX inhibitors that induce ferroptosis and inhibit triple-negative breast cancer metastasis. (PubMed, Bioorg Med Chem) - "Satisfyingly, this compound exhibited superior antitumor activities against MDA-MB-231 cells under hypoxia than normoxic conditions and surpassed reference compound SLC-0111...Notably, in vivo assays results demonstrated that 11o exerted efficient antitumor activity and significant anti-metastasis potency in a xenograft model of highly metastatic murine breast cancer 4 T1 cells. These findings suggest that 11o may serve as a potential candidate for combating triple-negative breast cancer metastasis."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CA9 • TOP1

Design, Synthesis, and In Vitro Anticancer Evaluation of Thiazole-Based Chalcones Linked to Sulfanilamide as Tumor-Associated Carbonic Anhydrase IX and XII Inhibitors. (PubMed, J Med Chem) - "Compound 5u emerged as the most potent, exhibiting strong inhibition of hCA IX/XII, outperforming acetazolamide and SLC-0111. ADME predictions indicated good solubility and oral bioavailability, while DFT calculations supported its electronic stability. These results highlight 5u as a promising lead for dual hCA IX/XII-targeted cancer therapy."

Journal • Preclinical • Breast Cancer • Colon Cancer • Colorectal Cancer • Melanoma • Oncology • Solid Tumor • CA9

Targeting CAIX in tumor microenvironment stimulates anti-tumor immune response (EACR 2025) - "However, the role of CAIX in regulating anti-tumor immune responses has not been extensively investigated, and thus, it was a goal of this study.Material and Spheroids of pancreatic ductal adenocarcinoma cells (PDAC) were established and treated with anti-CAIX combinatorial therapy using an inhibitor of CAIX enzymatic activity, SLC0111, and CAIX-specific antibody, M75... We found that besides the known effects of CAIX on the survival of tumor cells in hypoxia, the activity of this enzyme plays an important role in the suppression of anti-tumor immune responses. Thus, targeting CAIX may represent a new opportunity to create a favorable milieu for anti-tumor immune responses in the TME. Funding: The Slovak Research and Development Agency 20-0480."

Biomarker • Tumor microenvironment • Fibrosarcoma • Metabolic Disorders • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Sarcoma • Solid Tumor • CA9 • CD8 • IFNA1 • IFNG

Selective Inhibition of Carbonic Anhydrase IX and XII by Natural Coumarin Coladonin and Its Derivatives: Promising Antimelanoma and Antiglioblastoma Agents. (PubMed, ACS Med Chem Lett) - "Compound 7e exhibited better selectivity on hCA IX than acetazolamide (AAZ). Both compounds displayed significant antiproliferative effects, markedly better than those of the reference hCA IX/XII inhibitor SLC-0111 currently in clinical phase IIb. These results highlight coladonin 6 as a promising scaffold for developing selective hCA IX/XII inhibitors targeting hypoxic tumors."

Journal • Brain Cancer • Glioblastoma • Melanoma • Oncology • Solid Tumor • CA9

INHIBITION OF CARBONIC ANHYDRASE IX AS A NEW THERAPEUTIC STRATEGY IN MULTIPLE MYELOMA (EHA 2025) - "Altogether our preliminary findings demonstrate the therapeutic potential of CAIX inhibitors as single agents or in combination with proteasome inhibitors (PIs) for both naïve and PIs-refractory MM patients."

Hematological Malignancies • Metabolic Disorders • Multiple Myeloma • Oncology • Solid Tumor • ANXA5 • CA9

Low cellular pH promotes survival in CDK4/6 inhibitor resistant ER+ breast cancer (AACR 2025) - "Particularly, in abemaciclib resistant cells, intracellular pH is lower (pH=6.9) than that of sensitive cells (pH=7.4)...Small molecule inhibitor of CA9, S4 or the clinical-grade drug SLC-0111, inhibits growth and invasive potential in resistant cells when combined with CDK4/6i plus an antiestrogen...Furthermore, knockdown of HIF2α reduces CA9 protein expression and inhibits proliferation in resistant cells. Thus, our study highlights the role of the modulation of pH homeostasis as a mechanism for CDK4/6i resistant breast cancer and identifies CA9 and HIF2α as novel targets in treating advanced ER+ breast cancer."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CA9 • CDK4 • EPAS1 • ER

Discovery of a novel 4-pyridyl SLC-0111 analog targeting tumor-associated carbonic anhydrase isoform IX through tail-based design approach with potent anticancer activity. (PubMed, Front Chem) - "Docking confirmed strong CA IX binding, and ADMET analysis indicated good oral bioavailability. These results support Pyr as a promising anticancer candidate."

IO biomarker • Journal • Oncology • BAX • BCL2 • CA9

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. (PubMed, Bioorg Chem) - "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. 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."

Journal • PK/PD data • Hematological Malignancies • Leukemia • Melanoma • Oncology • Solid Tumor

Investigating the Anti-Inflammatory Potential of SLC-0111: A Carbonic Anhydrase Inhibitor Targeting Cyclooxygenase-Mediated Inflammatory Pathways in a Carrageenan-Induced Rat Model. (PubMed, J Biochem Mol Toxicol) - "However, SLC-0111 had no significant effect on MDA or GSH levels. These data represent that SLC-0111 may have anti-inflammatory properties and could be used as a treatment for inflammation-related disorders."

Journal • Preclinical • Asthma • Atherosclerosis • Cardiovascular • Diabetes • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Metabolic Disorders • Oncology • Pulmonary Disease • Respiratory Diseases • IL13 • IL1B • IL4 • IL6 • TNFA

Molecular dynamics simulation reveals structural insights into isozyme selectivity of carbonic anhydrase XII inhibitors in hypoxic tumor microenvironment. (PubMed, Biochem Biophys Res Commun) - "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...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."

Biomarker • Journal • Oncology

Design, Synthesis, and In Vitro Evaluation of Aromatic Sulfonamides as Human Carbonic Anhydrase I, II, IX, and XII Inhibitors and Their Antioxidant Activity. (PubMed, J Biochem Mol Toxicol) - "Most of the synthesized compounds showed significant inhibition in comparison to standard drugs such as acetazolamide, ethoxzolamide, zonisamide, methazolamide, dorzolamide, and SLC-0111. The in silico physicochemical properties, pharmacokinetic/ADME, and toxicity properties evaluations confirmed favorable drug-likeness properties, complying with Lipinski's rule. These findings underscore the therapeutic potential of these compounds for the treatment of retinal/cerebral edema, glaucoma, edema, epilepsy management, high-altitude sickness, and cancer."

Journal • Preclinical • CNS Disorders • Epilepsy • Glaucoma • Oncology • Ophthalmology

Novel benzenesulfonamide derivatives as potential selective carbonic anhydrase IX, XII inhibitors with anti-proliferative activity: Design, synthesis and in silico studies. (PubMed, Bioorg Chem) - "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...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,..."

Journal • CA9

Combination treatment with histone deacetylase and carbonic anhydrase 9 inhibitors shows therapeutic potential in experimental diffuse intrinsic pontine glioma. (PubMed, Brain Tumor Pathol) - "A synergy screen was conducted using CA9 inhibitor SLC-0111 and HDAC inhibitors panobinostat, vorinostat, entinostat, and pyroxamide. 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."

Epigenetic controller • Journal • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Solid Tumor • CA9

Benzoxaborinine, New Chemotype for Carbonic Anhydrase Inhibition: Ex Novo Synthesis, Crystallography, In Silico Studies, and Anti-Melanoma Cell Line Activity. (PubMed, J Med Chem) - "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."

Journal • Preclinical • Melanoma • Oncology • Solid Tumor

Breaking chemotherapy resistance in gastric adenocarcinoma: Immunogenic cell death induction by carbonic anhydrase IX targeting (ESMO 2024) - "When tumor resection is not possible, the perioperative chemotherapy (pCT) FLOT (Leucovorin, 5-Fluouracil, Docetaxel, and Oxaliplatin) represents the standard of care, at least in Europe, to enhance patients' overall survival. In summary, our findings indicate that the SLC-0111/FLOT combination therapy not only enhances treatment efficacy and restores sensitivity in resistant GC cells but also has the potential to induce ICD, which may stimulate an anti-cancer immune response to combat tumor progression."

Immunogenic cell death • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • ANXA1 • CA9 • CALR • HMGB1

Isocoumarins incorporating chalcone moieties act as isoform selective tumor-associated carbonic anhydrase inhibitors. (PubMed, Future Med Chem) - "They did not significantly inhibit off-target cytosolic isoforms hCA I and II (KI >100 μM) but acted as low micromolar or submicromolar inhibitors for the tumor-associated isoforms hCA IX and XII. Results & Our work provides insights into a new and scarcely investigated chemotype which provides interesting tumor-associated CA inhibitors, considering that some such derivatives like sulfonamide SLC-0111 are in advanced clinical trials for the management of metastatic advanced solid tumors."

Journal • Oncology • Solid Tumor

Discovery of novel 1,8-naphthalimide piperazinamide based benzenesulfonamides derivatives as potent carbonic anhydrase IX inhibitors and ferroptosis inducers for the treatment of triple-negative breast cancer. (PubMed, Bioorg Chem) - "The representative compound 9o exhibited more potent inhibitory activity and selective against CA IX over off-target CA II, compared with positive control SLC-0111...Notably, in vivo studies demonstrated that 9o effectively inhibited tumor growth and metastasis in a highly metastatic murine breast cancer 4 T1 xenograft model. Taken together, this study suggests that compound 9o represents a potent and selective CA IX inhibitor and ferroptosis inducer for the treatment of TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CA9

Breaking Chemotherapy Resistance in Gastric Adenocarcinoma: Immunogenic Cell Death Induction by Carbonic Anhydrase IX Targeting (EACR 2024) - "Material and Methods The CAIX inhibitor SLC-0111 and the standard European pCT FLOT (i.e. Leucovorin, 5-Fluouracil, Docetaxel, and Oxaliplatin) were used as single and combined treatments on wild-type (WT) and chemically-induced FLOT-resistant (FLOTr) GC cell lines. DAMPs analysis revealed increased levels of cytoplasmic dsDNA, expression of CALR and ANXA1, and increased release of HMGB1 and ATP by GC cells treated with SLC-0111/FLOT compared to control. Conclusion Overall, our data suggest that the SLC-0111/FLOT combination therapy not only strengthens therapy response and re-sensitizes resistant GC cells to therapy, but could also trigger immunogenic cell death that should prompt an anti-cancer immune response against tumor advancement."

Immunogenic cell death • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • ANXA1 • CA9 • CALR • DMRT1 • GPX4 • HMGB1

New sulfonamide-based glycosides incorporated 1,2,3-triazole as cytotoxic agents through VEGFR-2 and carbonic anhydrase inhibitory activity. (PubMed, Sci Rep) - "Sulfonamide-based derivatives, 4, 7 and 9 exhibited promising activity against HepG-2 and MCF-7 (IC50 = 8.39-16.90 μM against HepG-2 and 19.57-21.15 μM against MCF-7) comparing with doxorubicin (IC50 = 13.76 ± 0.45, 17.44 ± 0.46 μM against HepG-2 and MCF-7, rescpectively). Compoumds 7 and 9 gave favorable potency (IC50 = 1.33, 0.38 μM against VEGFR-2, 66, 40 nM against hCA IX and 7.6, 3.2 nM against hCA XII, respectively), comparing with sorafenib and SLC-0111 (IC50 = 0.43 μM, 53 and 4.8 nM, respectively). Moreover, the docking simulation was assessed to supply better rationalization and gain insight into the binding affinity between the promising derivatives and their targeted enzymes that was used for further modification in the anticancer field."

Journal • Oncology • KDR

SLC-0111-17-01: A Study of SLC-0111 and Gemcitabine for Metastatic Pancreatic Ductal Cancer in Subjects Positive for CAIX (clinicaltrials.gov) - P1/2 | N=6 | Terminated | Sponsor: British Columbia Cancer Agency | Phase classification: P1b ➔ P1/2 | N=30 ➔ 6 | Trial completion date: Aug 2025 ➔ May 2024 | Recruiting ➔ Terminated | Trial primary completion date: Feb 2025 ➔ May 2024; Changing treatment landscape: The availability of nab-paclitaxel with gemcitabine in the second-line setting has changed the feasibility of further recruitment and potential long-term development opportunities of SLC-0111 with gemcitabine alone.

Enrollment change • Phase classification • Trial completion date • Trial primary completion date • Trial termination • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CA9

In-vitro and in-silico investigations of SLC-0111 hydrazinyl analogs as human carbonic anhydrase I, II, IX, and XII inhibitors. (PubMed, Arch Pharm (Weinheim)) - "Both the series reported here were practically inactive against the off-target isozyme hCA I. Notably, derivative 10a exhibited superior potency (Ki of 10.2 nM) than acetazolamide (AAZ) against the cytosolic isoform hCA II. Compound 9g emerged as the most potent and selective hCA IX and XII inhibitor with Ki of 20.5 nM and SI of 200.1, and Ki of 6.0 nM and SI of 683.7, respectively, over hCA I. Furthermore, six compounds (9a, 9h, 10a, 10g, 10i, and 10j) exhibited significant inhibition toward hCA IX (Kis = 27.0, 41.1, 27.4, 25.9, 40.7, and 30.8 nM) relative to AAZ and SLC-0111 (Kis = 25.0 and 45.0 nM, respectively). These findings underscore the potential of these derivatives as potent and selective inhibitors of hCA IX and XII over the off-target hCA I and II."

Journal • Preclinical • Oncology

Targeting cellular pH as a novel therapeutic strategy in CDK4/6 inhibitor resistant breast cancer (AACR 2024) - "Of the three major CDK4/6i, only ribociclib and abemaciclib, but not palbociclib, have shown significant improvement in overall survival in the clinic. Small molecule inhibitor of CA9, S4 or clinical-grade SLC-0111, inhibits growth of resistant cells when combined with CDK4/6i plus antiestrogens. Thus, our study highlights the role of pH changes in CDK4/6i resistant breast cancer and offer therapeutic strategies to treat this incurable disease."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CA9 • ER