KOMM: Tackling drug resistant acute myeloid leukaemia with the next-generation FLT3 inhibitor

We have discovered a family of novel natural products from a sessile, bottom-living Arctic marine animal, and these compounds were found to inhibit the survival of selected cancer cell lines. After further examination, this activity was shown to be caused by inhibition of kinases. Kinases are key regulators of many biological processes, including cell division, and in many types of cancer kinases are over-expressed or over-active. By targeting specific types of cancers with kinase inhibitors, it is possible to stop uncontrolled cell division of cancer cells without affecting normal cells. The scaffold of the natural products we isolated from the marine animal was used as a starting point for production of synthetic analogues. We developed a new set of kinase inhibitors that are more potent and selective, but less toxic compared to the original natural products. We can now target just one specific type of blood cancer by inhibiting a specific mutated variant of a kinase, which is the cause of cancer in ~30% of these patients. In addition, some of the new variants have favourable drug-like properties, indicating that that they are well suited to be used by humans. Through this project we have produced new analogues with further improved drug-likeness of our front-running compounds. This include improved metabolic stability in order to prevent that the kinase inhibitors are removed from the body before they reach the cancer cells. The lead compound did demonstrate high tolerability and excellent efficacy in a xenograft mouse model of AML.

Acute myeloid leukemia is the most common type of aggressive adult leukaemia. Mutations in the FMS-like tyrosine kinase 3 (FLT3) kinase is the most common driver, found in 30–35% of all AML patients. Access to new treatment options for cancer is important to our society, and the importance of cancer to the UN SDG is further underlined by the announcement of EU mission on cancer, where “Diagnosis and treatment” is one of four mission objectives. Patients harboring the FLT3-ITD mutation have a particularly poor prognosis with increased risk of relapse and decreased chance of survival. Marketed FLT3 inhibitors all have insufficient inhibition of a variety of TKD mutations. This project has resulted in a lead candidate with activity against FLT-3 ITD and several drug resistant FLT-3 mutants, with improved and favorable pharmacokinetic and toxicological properties. The lead compound did demonstrate high tolerability and excellent efficacy in a xenograft mouse model of AML. This project did the initial optimization of the efficacy and pharmacokinetic properties, and could successfully nominate a lead compound for the next development phase. A start-up company is established to attract investors to develop this project into a preclinical development candidate.