Cathepsin proteases and cancer progression: A niche for dual-acting anticancer therapeutics

Cathepsin proteases have captivated the scientific community for many years owing to their deregulated expression, activation status, and potential role in the proliferation and progression of specific cancer types. These efforts have led to the development of several therapeutic strategies targeting specific cathepsin proteases. This development has been further driven by the identification of important cathepsin protease-specific target proteins. Despite the limitations of these approaches, primarily due to the lack of known specificity of cathepsin proteases in targeting substrate proteins, an alternative strategy may involve the identification and development of dual-acting therapeutics. We propose that these dual-acting therapeutics can selectively interfere with the protein constituents involved in forming a cathepsin-targeted protein complex while simultaneously inhibiting the cognate cathepsin protease. Considering this novel paradigm, we evaluated the potential of dual-acting therapeutics against other well-documented mimetic therapeutics designed to target intermediates in the apoptosis pathway. Some of these therapeutics may represent promising candidates for further testing as dual-acting anticancer therapeutics, either alone or in combination regimens.