cathepsin L inhibitors / Oncotelic, Baylor University - LARVOL DELTA

Cathepsin Protease Expression and Therapeutic Outcomes to Trastuzumab Deruxtecan (T-DXd) in Metastatic Breast Cancer (SABCS 2025) - " Using the Tempus database, the transcriptomic expression of two protease genes (cathepsin L "CTSL", cathepsin B "CTSB") was generated from pre-tx biopsies collected from patients with MBC (N = 453; 36% TNBC, 26% HR+/HER2-, 19.2% HER2+, 19% NOS) 1 year prior to or up to 15 days post-tx with SG (n = 204), T-DXd (n = 178), or T-DM1 (n = 71). Using a real-world multimodal dataset, here we build upon recent in-vitro findings and demonstrate the potential role of proteases as biomarkers of response to T-DXd in HER2 low/ultralow, but not HER2 positive/amplified breast cancer. These findings highlight the potential differential dependence on cathepsins based on HER2 expression and impact on payload release modulating efficacy in MBC. These findings need to be validated in additional datasets and can guide biomarker-driven clinical application of ADCs."

Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CTSB • CTSS • HER-2

Targeting anticancer agents to the tumor microenvironment with cathepsin B cleavable drug-linker conjugates of phosphatidylserine-binding proteins (AACR 2023) - "The payloads include benzosuberene-based aniline KGP156 and its phenolic congener KGP18, dihydronaphthalene-based KGP05, and indole-based OXi8006. Conjugation of thiolated Bavituximab with Mc-Val-Cit-PABC-KGP156 gave a drug/antibody ratio (DAR) of 3.6/1 after cleavage by cathepsin B and determination of released KGP156 by LC-MS. These studies revealed 1) distinct differences in cleavage rates for drug-linkers, 2) cleavage by cathepsin L, and 3) efficient cathepsin B mediated release of payload from the ADC."

Biomarker • Tumor microenvironment • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CTSB

Synthesis of Benzosuberene-based Compounds Designed to Function as Inhibitors of Tubulin Polymerization and Development of Drug Linker Constructs for Selective Targeting (ACS-Sp 2022) - "In preliminary studies, these small-molecule benzosuberene payloads were synthetically linked to dipeptide sequences terminating in a maleimido caproic acid moiety and evaluated in protease cleavage studies. Cleavable linker constructs that incorporate aniline-based payloads and the valine-citruline dipeptide (widely used in drug-linker constructs) were efficiently cleaved by cathepsin B and cathepsin L. The drug linker construct integrating the KGP156 payload demonstrated an average release (over 3 experiments) of the payload upon enzyme exposure (90 minutes) from NAC-Mc-Val-Cit-PABC-KGP156: 98% (cathepsin B); 95% (cathepsin L)."

Breast Cancer • Oncology • Solid Tumor • CTSB • CTSL

Functionalized small-molecule thiosemicarbazones as inhibitors of cathepsin K-mediated collagenase activity (AACR 2018) - "Recent studies have also confirmed that thiosemicarbazones have the ability to inhibit human and parasitic cathepsin L like-cysteine proteases and the mammalian cathepsin L. This work reports the investigation of a library of thiosemicarbazones synthesized to test their efficiency to inhibit human cathepsin K. Nine thiosemicarbazone (TSC) compounds had IC50 values of less than 50 nM against CatK using a fluorogenic assay with Z-L-Phe-L-Arg-AMC. The activity of CatK was greatly stabilized by the inclusion of chondroitin sulfate in the reaction mixture, but inhibition of the enzyme was not affected. These data indicate that potent, small-molecule TSC CatK inhibitors may be useful to prevent the metastatic spread of cancer to bone."

Breast Cancer • Melanoma • Sarcoma

Small-molecule inhibition of cathepsins L and K as potential therapeutics for macrophage-driven breast cancer (AACR 2018) - "In summary, the novel cathepsin L/K inhibitors KGP94 and KGP207 altered M0 to M2 differentiation, reduced macrophage invasion, and reduced macrophage-stimulated invasion of breast cancer cells. These data highlight the importance of cathepsin L in macrophage functions and suggest that cathepsin inhibition strategies may be therapeutically beneficial by impairing the progression of tumors, particularly those with high recruitment of M2 macrophages."

Breast Cancer