Dual Mechanism Kinase Inhibitors

Inflection Biosciences’ dual mechanism cancer drug program is the first of its kind rationally designed to target two well-known cancer pathways, PIM kinase and PI3K. Our first-in-class drug pipeline has potential utility in solid tumours such as breast cancer, lung cancer and in a range of blood cancers including CLL and acute myeloid leukaemia.

A powerful combination

PIM kinase (proto-oncogene proviral integration site for moloney murine leukemia virus) is known to be involved in critical cell signalling pathways that regulate processes including cell cycle progression, apoptosis and transcriptional activation. In recognition of the growing understanding of the role of PIM kinase in cancer there are now PIM kinase inhibitors in early stages of clinical development. 

Recent developments in cancer biology show that multiple targets likely need to be simultaneously targeted in cancer cells to prevent resistance and maximize activity. Experience with our own PIM kinase program indicated that it could usefully combine with inhibition of other signalling pathways to produce a significant reduction in cancer cell growth. Some of the most marked synergies were observed when PIM kinase inhibition was combined with inhibitors of PI3 kinase. The PI3K (phosphoinositide 3-kinase) signalling pathway plays a critical role in the regulation of cancer cell growth, survival and proliferation. Given the prevalence of the PI3K pathway in cancer it has been of considerable interest to the industry. Three PI3-kinase inhibitor drugs have already been approved (Zydelig®, AliqopaTM, Copiktra®) in leukemia/lymphoma, while a PI3K inhibitor has recently been approved for PIK3CA mutated breast cancer patients (PIQRAY®). 

Researchers at the Dana-Farber Cancer Institute recently sought to understand why many of the PI3K inhibitors had failed to deliver robust clincial outcomes for breast cancer patients. They have shown that while PI3K kinase inhibition is effective in arresting the growth of cancer cells, used alone it may allow surviving quiescent cancer cells to develop resistance, leaving a reservoir of cells that can regrow and cause the cancer to return (W. Hahn; eLIFE; May 2017).  This group demonstrated that co-targeting PIM kinase inhibition alongside PI3K inhibition converts the cell cycle arrest induced by PI3K inhibition into apoptosis.

Further evidence suggests that both PI3K and PIM kinase are involved in immune cell regulation, actively promoting and protecting cancer cells. PIM kinase isoforms defend cancer cells from therapeutic and immune attacks (E. Morales; Apoptosis; September 2016) while PI3K controls immune suppression (Vanhaesebroek; Cancer Discovery; October 2016). Inactivating both these pathways would complement the growing immunotherapy approaches (e.g. PD-1, PD-L1) which are becoming standard of care in a number of cancers.

Our approach is to achieve superior clinical effect by harnessing the power of PI3 kinase inhibition to slow tumour cell growth and combine it with PIM kinase inhibition that blocks the escape pathway for signalling in the cancer cells. This dual mechanism has the advantage of being more effective in arresting tumour cell growth, driving cancer cell death and preventing the emergence of the resistance that has been observed with PI3K inhibitors in the clinic.

Our pipeline

Our dual mechanism approach inhibits both PI3K and PIM kinases without affecting other kinases. The IBL-300 (AUM300) series are PIM/PI3k/mTOR inhibitors (partnered with AUM Biosciences) and our IBL-200 series are PIM/PI3k inhibitors. The macrocyclic chemistry underpinning our dual mechanism inhibitors confers a strong patent position and we have a granted composition of matter patent covering our molecules. Please visit AUM302 and IBL-202 to learn more.

Inflection Bioscience's unique dual mechanism inhibitor program has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement number: 868712. 

 

 





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