KULA18 has been engineered to inhibit pyruvate dehydrogenase kinase (PDK), a mitochondrial matrix based enzyme. By blocking PDK, KULA18 relieves the inhibition of pyruvate dehydrogenase (PDH) that PDK imparts. The PDH complex links glycolysis to the citric acid cycle and drives significant metabolism in a large number of cancers, especially in those tumors where PDK is highly expressed. PDK is a well-validated target in a variety of cancers, with PDK gene expression and copy number having been found to be predictive of disease progression and survival. KULA18 has been studied in a number of in vitro and in vivo models.
KULA19 is a targeted inhibitor of Hexokinase 2 (HK2), which localizes to the outer mitochondria membrane (OMM). HK2 is the first and rate-limiting step in glycolysis, the primary metabolic pathway supporting cancer cell metabolism. By phosphorylating glucose, HK2 prevents it from exiting the cell while at the same time committing it to glycolysis. In cancer cells HK2 has been shown to co-localize with VDAC at the OMM to more efficiently support glycolysis. By targeting HK2 at its specific site of actions provides a distinct advantage for KULA19. We have completed a number of pre-clinical studies with KULA19.
KULA200 is a small peptide targeted to inhibit the anti-apoptotic protein Bcl-2. Bcl-2 and its family members are located on the outer mitochondrial membrane, have been found to be highly over-expressed in a large number of cancers, and are critical for enabling cancer cells to bypass the apoptosis program that would otherwise limit proliferation and progression. KULA200 is one of a number of Bcl-2 family inhibitor we have in lead development and optimization.
KULA300 has been engineered to deliver one of the most utilized cancer chemotherapeutics, cisplatin, to the mitochondrial genome. Current treatment with cisplatin can often lead to resistance over time, a result of a number of DNA repair mechanisms that are in place in the nucleus. In the mitochondria there are no such repair mechanisms. We have found that targeting cisplatin to mitochondria can overcome cisplatin resistance. KULA300 has also been engineered to penetrate the blood-barrier-barrier, providing sought-after access to the brain to battle difficult-to-treat tumors, like glioblastoma, which are often some of the most fatal.
KULA-Vax is a unique application of our mitochondria-targeting platform with direct implications for improving cancer immunotherapy. For the most part, current methodologies, including chimeric antigen receptor t-cell (CAR-T) therapy, antibody-drug conjugates (ADCs) and monoclonal antibodies (mAbs) rely on a small subset of antigens as the basis for their targeting mechanisms. We have focused on expanding the antigen pool that can be utilized in these treatment paradigms, using our technologies to drive very specific mitochondrial pathways. Through our process, we have demonstrated the cancer-specific activation of both dendritic cells and T-cells with strong production of important immune modulators such as IL-12, IL-18 and TNF-alpha. We continue to develop our platform, which has applications across cancer immunotherapy modalities.
KULA101 is the first in our series of Tumor Microenvironment Modifiers (TMEMs) which we have shown in vivo to have the ability to lower multiple checkpoint proteins while inhibiting glycolysis specifically and directly in cancer cells. We believe this double hit would not only provide for a novel first-in-class therapeutic on its own, but would also be a strong enabling technology for CAR-T and other cell based therapies targeted solid tumors.