SLC-0111 / SignalChem Lifesci, Welichem - LARVOL DELTA

Multitargeted Anticancer Activities: Cathepsin B-Carbonic Anhydrase IX/XII Inhibitors Show Enhanced Cytotoxicity Against Lung Adenocarcinoma Cells. (PubMed, Arch Pharm (Weinheim)) - "Overall, respectively, three (KI < 25 nM) and two compounds (KI < 5.7 nM) showed better inhibition of hCA IX and XII as compared with reference drug acetazolamide. Compound 9f exhibited 35-fold and eightfold better hCA I/IX and hCA I/XII inhibition selectivity, respectively, as compared with SLC-0111. Likewise, all the synthesized compounds were also assayed for their inhibition profile against cathepsin B. Some compounds exhibited better inhibition of cathepsin B as compared with reference compound curcumin. In vitro cytotoxicity studies targeting non-cancerous Vero cells (green monkey kidney cells) and cancerous A549 cells (human lung adenocarcinoma cells) have also been performed, which showed interesting results."

Clinical • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CA9 • CTSB

1-Aryl-6,7-Dimethoxy-3,4-Dihydroisoquinoline-2(1H)-Sulfonamides as hCA XII Selective Inhibitors: Experimental and Theoretical Studies to Interrogate the Isoform Selectivity. (PubMed, ChemMedChem) - "Additionally, they showed remarkable isoform selectivity compared with the well-known inhibitor SLC-0111, currently in clinical trials as an antitumor agent. Crystallography analyses and computational studies clarified the molecular basis of this behavior and provided valuable insights for the rational design of selective inhibitors targeting hCA XII."

Journal • Oncology

Challenges and opportunities for developing selective carbonic anhydrase inhibitors and activators for vertebrate isoforms. (PubMed, Enzymes) - "Carbonic anhydrase (CA, EC 4.2.1.1) inhibitors of the sulfonamide/sulfamate type, such as acetazolamide, thiazides/high-ceiling diuretics, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, antiepileptics (sulthiame, topiramate, zonisamide), or non-steroidal anti-inflammatory agents such as celecoxib and polmacoxib, are effective inhibitors of most CA isoforms present in vertebrates but their clinical use in various pathologies is associated with side effects. Significant efforts were done in the last decades for developing isoform-selective inhibitors for all 12 catalytically active mammalian isoforms, with important results being obtained by using the tail approach or by the discovery of new inhibitory chemotypes, such as the coumarins and their derivatives, the boron/selenium-containing compounds, etc. SLC-0111, an antitumor sulfonamide in clinical development is an example of a successful strategy emerged by using the tail approach, this..."

Journal • Review • CNS Disorders • Cognitive Disorders • Mood Disorders • Obsessive-Compulsive Disorder • Oncology • Post-traumatic Stress Disorder • Psychiatry

Carbonic anhydrases I and II. (PubMed, Enzymes) - "Many CA inhibitors are in clinical use for the management of such conditions, among which are acetazolamide, thiazides and high-ceiling diuretics, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, and antiepileptics such as sulthiame, topiramate and zonisamide, whereas SLC-0111 is in clinical development as an antitumor agent. CA activators are not yet used clinically, but they might have pharmacological applications in the management of neurodegeneration, emotional memory disorders, obsessive-compulsive disorders, phobias, generalized anxiety, and post-traumatic stress. Finding novel modulators of activity for these enzymes may lead to innovative therapeutic applications and deepen our understanding of enzymes, their inhibitors, and their activators."

Journal • Review • Alzheimer's Disease • Cardiovascular • CNS Disorders • Cognitive Disorders • Epilepsy • Genetic Disorders • Glaucoma • Hypertension • Immunology • Inflammatory Arthritis • Mood Disorders • Neuralgia • Obesity • Obsessive-Compulsive Disorder • Obstructive Sleep Apnea • Oncology • Ophthalmology • Osteoporosis • Pain • Post-traumatic Stress Disorder • Psychiatry • Respiratory Diseases • Rheumatoid Arthritis • Rheumatology • Sleep Disorder

Design and Synthesis of Bendamustine-Carbonic Anhydrase Inhibitors with Antiproliferative Effects in Clear Cell Renal Cell Carcinoma. (PubMed, J Med Chem) - "Human carbonic anhydrase IX (hCA IX) is markedly overexpressed in clear cell renal cell carcinoma and plays a key role in establishing an acidic tumor microenvironment associated with intrinsic chemoresistance. The resulting compounds were evaluated against hCA I, II, IX, and XII, displaying preferential inhibition of the tumor-associated isoforms. Selected derivatives (13a and 14c) showed antiproliferative activity in 786-O and CAKI-1 cells, inducing cell-cycle arrest and reducing long-term proliferative capacity more effectively than the reference CA IX inhibitor SLC-0111."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CA9

Carbonic Anhydrase IX inhibitors as a new therapeutic strategy in multiple myeloma (EACR 2026) - "Thus the aim of this work is to investigate the anti-MM activity of two CAIX inhibitors, the clinical grade sulphonamide SLC-0111 (Phase Ib/II) and its analog FC-531.Material and The antiproliferative and proapoptotic effects of CAIX blockade were investigated by cytofluorimetric analyses through viable cell counting and Annexin-V/PI staining...To note, CAIX inhibitors combined with Bortezomib exerted an increased anti-myeloma activity compared to single treatments. Our 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 • Solid Tumor • ANXA5 • CA9

Molecular understanding for therapeutic targeting of hypoxia in breast cancer. (PubMed, Expert Opin Ther Targets) - "Apart HIF itself, other potential molecular targets such as prolyl-hydroxylases (PHD), von Hippel-Lindau protein (VHL), monocarboxylate transporters (MCTs), Na+ /H+ exchangers (NHEs), vacuolar ATPases (V-ATPase), anion exchangers (AEs), Na+ /HCO₃- co-transporters (NBCs), vascular endothelial growth factor (VEGF) and carbonic anhydrases were identified as being involved in tumorigenesis. HIF-1α inhibitors (topotecan, digoxin, PX-478), hypoxia-activated prodrugs (evofosfamide, apaziquone, porfiromycin, tirapazamine, banoxantrone) and carbonic anhydrase IX/XII inhibitors (SLC-0111) are either used clinically or in clinical development for the management of hypoxic breast cancers."

Journal • Review • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • Von Hippel-Lindau Syndrome • CA9 • HIF1A

Carbonic Anhydrase Inhibitors in Oncology. (PubMed, Subcell Biochem) - "This has prompted an effort to inhibit specific CA isoforms, as an anticancer therapeutic strategy with small molecule inhibitors, one of which (SLC-0111) completed Phase I clinical trials...Beyond small-molecule inhibitors, antibody-based approaches have reached clinical and preclinical development as imaging agents, radioimmunotherapeutics, antibody-drug conjugates, and nanomaterial conjugates. Collectively, these strategies highlight the potential of exploiting the metabolic vulnerabilities of hypoxic tumors by co-targeting CA IX/XII with complementary redox or survival pathways, paving the way toward rational polypharmacology in precision oncology."

Journal • Review • Metabolic Disorders • Oncology • CA9

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

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

Expanding the Inhibitory Potential of the Benzoxaborinine Scaffold against Carbonic Anhydrases: Synthesis, Structural Characterization, and In Vitro Antitumor Activity. (PubMed, J Med Chem) - "X-ray crystallographic analysis of the complexes of 2H-benzoxaborinine 2a with hCA I and hCA II revealed significant differences compared with the 1H-benzoxaborinine analogue, which can be attributed to the increased structural rigidity of the scaffold. Finally, the selected compounds (2a, 3d, 5c, and 9c) were further evaluated for their in vitro antiproliferative activity against human triple-negative breast cancer (MDA-MB-231) and glioblastoma (U87MG) cancer cell lines, with derivative 5c demonstrating superior antiproliferative activity compared with the antitumor CA inhibitor SLC-0111."

Journal • Preclinical • Brain Cancer • Breast Cancer • Glioblastoma • Oncology • Solid Tumor • Triple Negative Breast Cancer

Interpretable machine learning rationalizes carbonic anhydrase inhibition via conformal and counterfactual prediction. (PubMed, Sci Rep) - "To further test our model capability, we examine it on SLC-0111, as a selective inhibitor, which leads to a compatible result with the experiment. Our model reiterates experimental findings that modifications in the tail region strongly affect molecular selectivity, emphasizing the tail group as a key structural determinant for differentiating inhibitor activity among hCA isoforms II, IX, and XII. To facilitate adoption, we also release CAInsight, a user-friendly software with a graphical interface for virtual screening and generative design of a selective hCA inhibition."

Journal • Oncology

The Hypoxic niche shapes cancer-associated fibroblast heterogeneity in hepatocellular carcinoma and uncovers a therapeutic vulnerability (LCS 2026) - "The combination of Atezolizumab (anti–PD-L1) and Bevacizumab (anti– VEGF) (AtezoBev) exhibits improved survival compared to previous standard-of-care treatments; however over 70% of patients display refractory responses, with minimal benefit or disease progression within six months...Pharmacological interventions using SLC-0111 (carbonic anhydrase IX inhibitor) or an ALK5 inhibitor (TGFβ receptor I blockade) were applied at mid-stage tumour development...ALK5 inhibition reduced intratumoral collagen, increased CD8⁺ T-cell recruitment, and shifted CAF composition toward a more quiescent phenotype, suggesting suppression of CAF activation through TGFβ pathway inhibition. Conclusion Collectively, these findings identify hypoxia-driven CAF plasticity as a critical mechanism of immunotherapy resistance in HCC and support a therapeutic framework in which CAF-targeted interventions precede immunotherapy to reprogram the tumour microenvironment for improved clinical outcomes."

Heterogeneity • IO biomarker • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CA9 • CAFs • CD8 • HIF1A • TGFB1 • TGFBR1

Targeting Metabolic and pH Regulatory Pathways in Cancer via Dual Inhibition of Nicotinamide Phosphoribosyltransferase and Carbonic Anhydrases IX and XII. (PubMed, J Med Chem) - "In three-dimensional (3D) spheroids, compound 45 reduced the cumulative spheroid area approximately 10-fold more than the single-target inhibitors FK866 or SLC-0111 and induced apoptosis through NAD depletion, mitochondrial dysfunction, and suppression of ERK/mTOR signaling. These results support dual hCA IX/XII-NAMPT inhibition as an effective strategy to impair tumor growth and survival under hypoxic stress."

Journal • Brain Cancer • Colorectal Cancer • Glioblastoma • Kidney Cancer • Metabolic Disorders • Oncology • Renal Cell Carcinoma • Solid Tumor • NAMPT

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

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