SLC-0111

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.

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.

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.

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.

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.

Docking confirmed strong CA IX binding, and ADMET analysis indicated good oral bioavailability. These results support Pyr as a promising anticancer candidate.

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.

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.

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.

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.

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.