The metalloenzyme target Carbonic Anhydrase IX (CAIX) is expressed on the cell surface of hypoxic (oxygen depleted) tumour cells particularly cancer stem cells, and is one of the major factors contributing to the cancer cell survival and metastasis. The role of CAIX is to catalyze the reversible hydration of carbon dioxide to bicarbonate and protons:
H2O + CO2 → HCO3- + H+
In a low oxygen environment, the cancer cell switches from aerobic metabolism to anaerobic metabolism and this leads to production of acidic bi-products and an excess of protons (H+) which generates acidosis in the cell. In normal circumstances, the cancer cell would die due to the internal acidic environment. However, CAIX removes the excess protons from the cell thereby ensuring that the pH remains neutral (non-acidic) and favourable to facilitating cancer cell survival. Moreover, the removal of the access protons to the outside of the cancer cell by CAIX leads to an increased acidic extracellular environment which then leads to two critical outcomes. First, the acidic environment provides a protective barrier to counteract against the effects of chemotherapy and radiation therapy in their ability to kill these cancer cells and second, the acidic environment leads to activation of extracellular metalloproteases which facilitate the degradation of extracellular matrix thereby allowing the cancer cells to migrate to secondary sites. CAIX is thus a critical regulator of the intracellular pH (via the hydration process) of cancers cells in hypoxic regions which is essential for cancer cell growth, survival and metastasis and it is for this reason that inhibition of CAIX results in apoptosis of cancer stem cells and an inability for these cancer cells to metastasis.
CAIX is a critical component of highly resistant cancer cells such as cancer stem cells and is preferentially utilized by these cells for survival and spread to secondary sites. CAIX expression has been detected in at least 14 types of human cancers including breast, renal, lung, colon, thyroid, bladder, oesophageal, oligodendroglial and cervical cancers. Selective inhibition of CAIX using shRNA in cell and animal models has shown significant decrease in tumour cell survival and metastasis.
SLC-0111 is a first-in-class small molecule which selectively inhibits Carbonic Anhydrase IX (CAIX). The phase Ia clinical trials in multi-centers in Canada to establish a maximum tolerable dose and pharmacokinetics in cancer patients was completed and the phase Ib clinical trials with pancreatic patients in combination with gemcitabine will be initiated in Q3 2018. SLC has entered into a partnership to develop this compound with Welichem Biotech Inc.
SLC-149 is a small molecule derived from a structurally distinct novel chemical scaffold. It is currently in the pre-clinical stage to establish its efficacy in different animal models and in syngeneic models to evaluate its potential application in immuno-oncology. The anticipated timeline for the initiation of clinical trials of this compound is Q4 2019.