This pathway is controlled by the BCL-2 family of proteins, which contains both pro-apoptotic and pro-survival members that balance the decision between cellular life and death. The interplay of pro-survival and pro-apoptotic elements of the pathway is tightly regulated.
Both the up-regulation of pro-survival elements and the down-regulation of apoptosis, favoring the pro-survival elements of the pathway, drive the survival of cancer cells. Both can be exploited for targeted treatment in cancer.
To date, the therapeutic focus has been on targeting the pro-survival proteins, BCL-2, BCL-XL and MCL-1. This indirect approach of “inhibit the inhibitor” strategy has been effective for treatment of certain leukemias, with venetoclax.
However, the development of resistance in hematological malignancies, and the inability to dose to therapeutic efficacy in solid tumors, has prevented scientists from exploiting the full therapeutic potential of this pathway.
BAKX overcomes the above challenges in targeting Pro-Survival proteins by:
Our scientific founders elucidated the trigger site on inactive BAX enabling the discovery of direct small molecule BAX-activators. The first BAX activator molecule was discovered through in silico screening (Gavathiotis et al., Nat Chem Biol 2012, 8, 639) and developed through medicinal chemistry as a tool compound that binds with high affinity and specificity to the BAX trigger site. Further optimization is enabled by the BAKX CoDynX™ Platform using cutting-edge computational tools and structural design underpinned by extensive medicinal chemistry efforts.
Leveraging our knowledge of the BAX protein and our CoDynX™ platform we are also developing inhibitors of BAX to target Neurodegenerative and other age related diseases.
BCL-XL is a critical apoptosis target with strong relevance across several solid tumors (including NSCLC, colorectal, and pancreatic cancers). It is an effective mechanism of resistance to chemotherapy and other apoptosis-inducing agents. But the clinical application of BCL-XL inhibitors has been challenging due to dose-limiting thrombocytopenia.
BAKX is driving a new generation of BCL-XL inhibitors that could overcome the issues of platelet toxicity, enabled by the CoDynX™ platform coupled with a solid understanding of the BCL-XL protein and the apoptosis pathway. We also see a strong synergy for BCL-XL inhibition with our BAX activator – as shown by our co-founder Evripidis Gavathiotis – Lopez A., Reyna, D.E., Gitego, N. et al.. Nat Commun 13, 1199 (2022).
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August 13, 2021
