The lead inhibitors reached 2 pM affinity, the highest among known CAIX inhibitors. The strategy could be used for any disease drug target protein bearing a His residue in the vicinity of the active site.

[89Zr]ZrDFOSq-girentuximab has high uptake in CAIX positive tumours. An automated procedure for the synthesis of [89Zr]ZrDFOSq-girentuximab using [89Zr]ZrCl4 as a starting material has been developed. This automated process could be readily adapted to other antibodies.

Therefore, the chromene-linked bis-indole derivatives can serve as a novel non-sulfonamide class of tumor-associated hCA IX inhibitors.

There will be significant change in the field of imaging in RCC as molecular imaging becomes increasingly popular, which reflects a shift in management to a more conservative approach, especially for small renal masses (SRMs). There is the hope that the improvement in imaging will result in less unnecessary invasive surgeries or biopsies being performed for benign or indolent renal lesions.

Our results suggest that [89Zr]Zr-girentuximab PET-CT has a favourable safety profile and is a highly accurate, non-invasive imaging modality for the detection and characterisation of clear-cell renal cell carcinoma, which has the potential to be practice changing.

On the other end of the spectrum, carbonic anhydrase IX agents, most notably the monoclonal antibody girentuximab - which can be labeled with positron emission tomography radionuclides such as zirconium-89 - are effective at identifying renal masses that are likely to be aggressive clear cell renal cell carcinomas...The combination of molecular imaging and biopsy in selected patients with other advanced imaging methods, such as artificial intelligence/machine learning and the abstraction of radiomics features, offers the optimal way forward for maximization of the information to be gained from risk stratification of indeterminate renal masses. With the proper application of those methods, inappropriately aggressive therapy for benign and indolent renal masses may be curtailed.

Among the derivatives, 10a, 10c, and 10e exhibited potent cytotoxicity against PC-3 cells with IC50 values of 2.08, 7.57, and 5.52 μM compared to doxorubicin (IC50 = 2.31 μM) with potent inhibition of CA IX with IC50 values of 0.113, 0.134, and 0.214 μM. The most active compound, 10a, was tested for apoptosis-induction; it induced apoptosis by 31.9-fold cell cycle arrest at the G1-phase. Further, the molecular modeling approach highlighted the relevant binding affinity for the top-active compound 10a against CA IX as one of the most prominent PC-3 prostate cancer-associated biotargets.

P1/2, N=170, Recruiting, Debiopharm International SA | Trial completion date: Jan 2027 --> Mar 2029 | Trial primary completion date: Jan 2026 --> Jun 2027

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.

This study demonstrates that [89Zr]Zr-DFO-girentuximab administered to Japanese patients with suspected RCC has a favorable safety profile and is well tolerated and has a similar dosimetry profile to previously studied populations.

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.

P1/2, N=6, Terminated, 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.

P=N/A, N=17, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Apr 2024 --> Apr 2025 | Trial primary completion date: Apr 2024 --> Apr 2025

P1, N=36, Recruiting, Telix Pharmaceuticals (Innovations) Pty Limited | Phase classification: P1b --> P1

Molecular docking studies were performed to demonstrate the presence of numerous hydrogen bonds and hydrophobic interactions between the compounds and the active site of hCA. Absorption, distribution, metabolism, excretion (ADME) predictions showed that all of the compounds had good pharmacokinetic and physicochemical properties.

[177Lu]Lu-DPI-4452 demonstrated strong tumor growth inhibition in 2 xenograft mouse models. Thus, the 2 agents potentially provide a theranostic approach for selecting and treating patients with CAIX-expressing tumors such as ccRCC, CRC, and pancreatic ductal adenocarcinoma.

Mechanistic investigation using western blotting revealed compound 8q exerted the anti-migrative and anti-invasive effects probably through mitochondria-mediated PI3K/AKT pathway by targeting CAIX. In summary, coumarin-3-sulfonamide derivatives were developed as potential and effective CAIX inhibitors, which were worthy of further investigation.

This new H2MacropaSqOEt chelator was used to modify a monoclonal antibody, girentuximab (hG250), that binds to carbonic anhydrase IX, an enzyme that is overexpressed on the surface of cancers such as clear cell renal cell carcinoma...Evaluation of [225Ac]Ac(MacropaSq-hG250) in a mouse xenograft model, that overexpresses carbonic anhydrase IX, demonstrated a highly significant therapeutic response. It is likely that H2MacropaSqOEt could be used to modify other antibodies providing a readily adaptable platform for other actinium-225 based therapeutics.

Our study successfully applied computational strategies to discover three non-sulfonamide inhibitors of carbonic anhydrase IX (CA IX) that demonstrate inhibitory activity in vitro. These findings have significant implications for the development of CA IX inhibitors and anti-tumor drugs, contributing to their progress in the field.

[68Ga]Ga-DPI-4452, a first-in-class carbonic anhydrase IX-binding radiolabeled peptide, is the imaging agent of a theranostic pair with [177Lu]Lu-DPI-4452, developed for selecting and treating patients with carbonic anhydrase IX-expressing tumors...No clinically significant toxicity was observed. [68Ga]Ga-DPI-4452 showed exceptional tumor uptake in patients with clear cell renal cell carcinoma, with very high tumor-to-background ratios and no significant adverse events, suggesting potential diagnostic and patient selection applications.

The IC50 values of J16 for MDA-MB-231 and MCF-7 cells, under normoxic condition were 6.3 and 3.7 µM respectively, which are 1.9/3.3 and 15.8 times better than U-4-Nitro and SLC-0111 respectively...Expression of the other apoptosis markers Bcl-2, Bim, caspase 9 and caspase 3 substantiated the apoptosis mechanism. However, decreased transcription/expression of HIF1A/HIF-1α and hCA-IX/XII also implies the inhibition of the extracellular signal-regulated kinase pathway by J2 and J16.

P1/2, N=100, Active, not recruiting, M.D. Anderson Cancer Center | Suspended --> Active, not recruiting | Phase classification: P2 --> P1/2

TThese results propose that the MMH-1 compound could triggers apoptosis in MDA-MB-231 cells via the pH/MMP/ROS pathway through the inhibition of CA IX. This compound is thought to have high potential and promising anticancer properties in the treatment of aggressive tumors.

P2, N=100, Suspended, M.D. Anderson Cancer Center | Recruiting --> Suspended

P2, N=100, Recruiting, M.D. Anderson Cancer Center | Phase classification: P1b/2 --> P2

Many studies in multiple solid tumour models have demonstrated that targeting CAIX activity with the selective CAIX/XII inhibitor, SLC-0111, results in anti-tumour efficacy, particularly when used in combination with chemotherapy or immune checkpoint blockade, and has now advanced to the clinic...Importantly, the data from these models demonstrates that CAIX inhibition may sensitize tumour cells to cytotoxic drugs and evidence now points to ferroptosis, an iron-dependent form of regulated cell death (RCD) that results from accumulation of toxic levels of phospholipid peroxidation as a major mechanism involved in CAIX-mediated sensitization to cancer therapy. In this mini-review, we discuss recent advances demonstrating the mechanistic role CAIX plays in sensitizing cancer cells to ferroptosis.

[68Ga]Ga-DPI-4452 provides exceptional images in patients with ccRCC without clinically significant toxicity. Very high SUVs and tumor-to-background ratios suggest potential for use in both diagnostics and patient selection for therapy. The tumor retention and rapid elimination support potential of [177Lu]Lu-DPI-4452 radioligand therapy.

The combination of nivolumab plus cabozantinib was recently approved for the first-line treatment of ccRCC based on the CheckMate 9ER phase 3 study demonstrating improved progression-free survival (PFS) & objective response rate (ORR) in comparison to sunitinib...To explore the effects of the treatment on inducing activated T cell infiltration, patients will undergo pre/post-treatment PET scan with [18F]F-AraG radiotracer as well as biopsies for single cell, spatial transcriptomics and proteomics studies. Clinical trial information: NCT05239533.

These findings suggest that S100P could serve as a promising biomarker for immunosuppressive microenvironment, which may provide a novel therapeutic way for pancreatic cancer.

The presence of a 4-F-CH moiety, also found in SLC-0111, afforded an excellent selectivity towards the tumor-associated hypoxia-induced hCA isoform XII with an inhibition constant (K) of 4.5 nM. The 2-naphthyl derivative was the most potent inhibitor against hCA IX (K = 6.2 nM), 4-fold stronger than AAZ (K = 25 nM) with very good selectivity. Some compounds were chosen for antiproliferative activity testing against a panel of 3 human tumor cell lines, one compound showing anti-proliferative activity on glioblastoma, triple-negative breast cancer, and pancreatic carcinoma cell lines.

In a cohort of GC patients who received perioperative FLOT (i.e., Leucovorin, 5-Fluouracil, Docetaxel, and Oxaliplatin) or FOLFOX (i.e., Leucovorin, 5-Fluouracil, and Oxaliplatin), non-responder patients showed an increased expression of tumor CAIX compared to responder group. Moreover, GC cell lines induced to be resistant to 5-Fluouracil, Paclitaxel, Cisplatin, or the combination of 5-Fluorouracil, Oxaliplatin, and Docetaxel, overexpressed CAIX compared to the control...Notably, SLC0111 significantly improved the therapy response of both wild-type and resistant GC cells. Overall, these data suggest a correlation between CAIX and GC drug resistance highlighting the potential of SLC-0111 in re-sensitizing GC cells to pCT.

Promising candidates were assessed for VEGFR-2 inhibition and selectivity and further evaluated on breast cancer cell lines (MCF-7 and T-47D) and the non-tumorigenic (MCF-10A) cells. Molecular docking studies explored the binding modes of the sulfonamides against hCA IX/XII and VEGFR-2 kinase.

A host of new preclinical data and several clinical trials of antibodies and small molecule inhibitors are ongoing, which connected with the large number of new chemotypes/procedures discovered to be effective, may lead to a breakthrough in this therapeutic area. The scientific/patent literature has been searched for on PubMed, ScienceDirect, Espacenet and PatentGuru, from 2018 to 2023.

P1b, N=30, Recruiting, British Columbia Cancer Agency | Suspended --> Recruiting | Trial completion date: Dec 2024 --> Aug 2025 | Trial primary completion date: Jul 2024 --> Feb 2025

SLC-0111, a ureido benzenesulfonamide, is a selective human carbonic anhydrase (hCA) IX inhibitor in clinical trials for the treatment of hypoxic malignancies...Thereafter, Annexin V-FITC apoptosis detection, cell cycle, TUNEL, and qRT-PCR, colony formation, and wound healing assays were applied to gain mechanistic insights and to understand the behavior of colorectal cancer cells upon the treatment of compound 8g. Also, a molecular docking analysis was conducted to provide in silico insights into the reported hCA IX inhibitory activity and selectivity.

P1b/2, N=100, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting | Initiation date: May 2024 --> Jun 2023

Altogether, these findings suggest S4 as a novel ICD inducer in glioma and might have implications for S4-based immunotherapy. Video Abstract.

P1b/2, N=100, Not yet recruiting, M.D. Anderson Cancer Center | Initiation date: May 2023 --> May 2024

The model considers treatment with the small molecule CAIX inhibitor SLC-0111 in combination with ICIs...Concluding, we have developed a model that reproduces experimental findings and enables the investigation of combination therapies. Our model suggests that transient CAIX inhibition may induce tumor regression, given a sufficient immune infiltrate in the tumor, which can be boosted with ICIs.

No abstract available

No abstract available

Inhibition of CA IX by SLC-0111 reduced the expression levels of PDL-1, p-STAT3, and Glut-1, and reversed TE-ADSC-induced acidic TME in TNBC cells.ConclusionTaken together our results demonstrate the crucial role played by TE-ADSCs in promoting immune surveillance by inducing an acidic TME in TNBC. Furthermore, we highlight the possibility to sensitize tumor cells to ICIs by targeting CAIX using SLC-0111.