PIM/FLT3 dual inhibition

The kinase inhibitor drugs era opened in 2001 with the approval of Imatinib. Since then over 30 small molecule kinase inhibitors (SMKI) (as for April 2016), were approved by the US Food and Drug Administration agency (FDA).

From the very beginning of the SMKI presence on the market, a discussion on superiority of selective inhibitors against multi-target ones has been taking place. Selective kinase inhibitors fit perfectly into the targeted therapy paradigm. By blocking signalling pathway at a precisely selected point – the kinase target – we should be able to eliminate cancer cells, at the same time not interfering with the healthy ones. However numerous approved drugs, including Imatinib, target multiple kinases. This kind of approach makes sense when you realise that cancer signalling is usually very complex and inhibiting just one, even a crucial kinase, may not result in a desired therapeutic effect. In fact, the therapeutic process is even more complex, since many cancers are very genetically unstable and may adopt to the treatment by development of resistance, achieved often by mutation of a targeted kinase or finding new signalling pathways. On the other hand, targeting multiple kinases increases the risk of causing side effects caused by an inhibition of a kinase responsible for processes vital for the patient organism.

One can imagine an ideal situation would be to target not one, and not many, but only those few kinases responsible for signalling in the cancer type we want to cure. Unfortunately, this “simple” solution is not that easy to implement. The reason for that is the fact that the binding sites of most kinases are very similar, which makes it difficult to obtain selective ATP competitive inhibitors (most approved SMKI are ATP competitive – type 1 or 2 – inhibitors). This concept is well realised, for example, in the dual EGFR/HER2 inhibitor Lapatinib or the mTOR/Pi3K^{i, ii} inhibitor NVP-BEZ235 (under development), as well as in SEL24 – a dual PIM/FLT3 inhibitor developed by Selvita. The FLT3 kinase is a well-known target in the treatment of AML (Acute Myeloid Leukaemia), with Quizartinib being probably the most investigated FLT3 inhibitor. At the same time, PIM kinases are a relatively new and very promising target in AML (and also other types of cancer).

At this point, it is important to name a basic issue with probably all of the targeted cancer therapies. By definition they target cells with specific genetic profile, identified as malignant. This improves their safety profile, but also narrows down the number of disease cases which will respond to the therapy. What is even worse, treatment may cause clonal selection of mutants resistant to the chosen therapy resulting in growing resistance.

SEL24, dual PIM/FLT3 inhibitor, combines two of the currently most promising targets in new therapies of AML. This should result in activity in a broader spectrum of cases (its activity was confirmed in animal studies on a broad spectrum of FLT3 mutated cells lines, as well as in FLT3 wild type models). It was also shown that PIM governs mutated FLT3 signalling, and that their inhibition restores cell sensitivity to FLT3 inhibitors.ⁱⁱⁱ This may translate into a mechanism which will make building up a resistance more difficult. Additionally, it may open up the possibility of treatment of other inhibitor resistant cases.

References

1. Liu, TJ; Koul, D; Lafortune, T; Tiao, N; Shen, RJ; Maira, SM; Garcia-Echevrria, C; Yung, WK (2009). “NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas“. Molecular cancer therapeutics 8 (8): 2204–10. doi:10.1158/1535-7163.MCT-09-0160
2. Serra, V; Markman, B; Scaltriti, M; Eichhorn, PJA; Valero, V; Guzman, M; Botero, ML; Llonch, E (2008). “NVP-BEZ235, a Dual PI3K/mTOR Inhibitor, Prevents PI3K Signaling and Inhibits the Growth of Cancer Cells with Activating PI3K Mutations”. Cancer Research 68 (19): 8022–30. doi:10.1158/0008-5472.CAN-08-1385
3. Sci Adv. 2015 Sep 18;1(8):e1500221. doi: 10.1126/sciadv.1500221