AK-423 is a protein-protein interaction modulator. It inhibits the lipogenic enzyme ACC (acetyl-CoA carboxylase) which plays an essential role in regulating fatty acid synthesis and degradation. High ACC expression is associated with worse overall survival (OS).
The cytoskeleton is a complex network of interlinking protein filaments. The components of the cytoskeleton include actin (microfilaments), microtubules and cytoskeletal-associated proteins. In normal cells, components of the cytoskeleton are highly integrated, and their functions are well regulated. The cytoskeleton has many functions, however, of importance to us is its ability to give the cell its shape and mechanical resistance to deformation and allowing cells to migrate.
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ACC inhibition improves the cellular uptake of cancer therapies. ACC inhibition reverses the phenotype of the cancer cell membrane back to normal phenotype; impairing cancer’s ability to metastasize. In addition, ACC inhibition slows the formation of cancer stem cells (CSCs), which are resistant to therapy and are responsible for cancer relapse. Lipogenesis is specific to cancer since most normal cells get their lipid needs from the diet. Lipogenesis inhibition is an ideal target for aggressive metastatic cancers.
In some cancers, cell deformability and its ability to move and migrate creates metastatic cancers. Metastasis (movement of cancer cells from one site to another) is responsible for the greatest number of cancer deaths. Metastasis requires drastic remodeling of the cytoskeleton where mutations and abnormal expression of cytoskeletal and cytoskeletal-associated proteins are common. These changes give cancer the ability to resist chemotherapy and metastasize.
Cancer cells are highly dependent on de novo fatty-acid synthesis (lipogenesis), a process that is usually suppressed in normal cells. Increased de novo lipogenesis is a hallmark of cancer and is proven to be linked with cancer risk and progression, and it protects cancer cells by rendering them less susceptible to therapy.
De novo lipogenesis in cancer changes the composition of the cell membrane and transforms it into a phenotype distinct to cancer. Membrane composition strongly regulates cell deformability, which correlates to the metastatic potential of some cancer types.
The microtubules and actin communicate through complex mechanisms to contribute to cell migration. We are interested in targeting such crosstalk/interaction between the various cytoskeletal components as an avenue to treat metastatic cancers. AK-321 is a targeted protein-protein interaction modulator that inhibits the interaction between the actin microfilament and the microtubules. In addition, AK-321 interacts with some of the cytoskeletal-associated proteins, as well as Focal adhesion kinase (FAK) protein. FAK activity correlates with increased clinical progression of cancer to highly metastatic phenotypes. It is also implicated in helping cancer evade the immune system, protecting cancer from therapy, and mediating recurrence/relapse by enhancing the capabilities of cancer stem cells (CSCs). AK-321 potency is in the picomolar range and is expected to limit the spread of metastatic tumors.