P1, N=24, Not yet recruiting, Institut Cancerologie de l'Ouest

[89Zr]Zr-girentuximab PET/CT is a sensitive imaging method and offers promise for novel theranostics for mTNBC patients.

A recent phase III trial (ZIRCON) is widely believed to have laid the groundwork for United States Food and Drug Administration approval of the CAIX monoclonal antibody 89Zr-girentuximab...Further, emerging new targeted radiotracers and techniques such as imaging biomarker discovery with artificial intelligence will bolster those concepts. In this manual, we synthesize key data into a recommended approach.

P1/2, N=100, Recruiting, M.D. Anderson Cancer Center | Trial primary completion date: Oct 2025 --> Oct 2027

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.

P3, N=40, Not yet recruiting, Telix Pharmaceuticals (Innovations) Pty Limited

Recombinant-enzyme assays validated these predictions: SB-203207, SB-203208 and sulfadixiamycin A inhibited CA IX esterase activity with IC₅₀ = 73 ± 1, 99 ± 2, and 114 ± 3 nM, respectively, versus 41 ± 1 nM for reference acetazolamide...SwissADME/ADMETlab profiling highlighted SB-203207 as the most developable hit. Together, these results establish entrance-channel plugging as an alternative mechanism for CA IX inhibition, identify SB-203207 as a potent and isoform-selective lead.

Moreover, X-ray crystallography data provided insights into the CA inhibition mechanism, suggesting that these compounds behave similarly to classical CAIs. In summary, this original TDP pharmacophore effectively inhibits human CAs, with relative selectivity towards hCA IX over cytosolic isoforms, thus providing structural insights for the development of a new class of selective anticancer agents.

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.

The use of SLNB has transformed nodal staging in PeC, influencing treatment decisions and reducing morbidity in patients undergoing surgery. In other urological malignancies, it has not yet established itself as a standard tool for nodal staging. Its impact on survival, quality of life, and translational research remains to be determined.

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.