PIK-001 a Novel Small Molecule Inhibitor of Pikfyve for Treatment of Multiple Myeloma (MM)

We utilized ex vivo chemo-genomics screening to identify potentially unrecognized targets of plasma cell biology. Medium throughput screening on MM and NHL cell lines was conducted using a panel of known FDA-approved oncology drugs, kinase inhibitors, and epigenetic compounds assembled by the investigators. A refined panel was then selected and sensitivity to the single agents was evaluated in 25 MM and 15 NHL cell lines. One panel drug APY-0201 and related drugs such as apilimod were initially developed as suppressors of production of interleukin (IL)-12 and IL-23 production and entered clinical trials for inflammatory diseases but subsequently were found to be primary inhibitors of PikFyve. We have previously published a dose dependent inhibition of cellular viability in all 25 MM cell lines exposed to the PIKfyve inhibitor APY-0201, with a median EC 50 of 55 nM and a median maximum inhibition of cellular viability of 81%. We next tested 100, ex vivo primary CD138+ selected, patient samples. Dose-dependent sensitivities for APY-0201 were observed in 40% of ex vivo samples at only 24 h, with 47% exhibiting an EC 50 lower than 100 nM. The sensitivity to both APY0201 and apilimod was examined in 15 ex vivo primary patients' samples after a longer 72 h incubation, and more significant anti-MM activity was noted with over 90% of the primary patients' samples showed dose dependent inhibition of cellular viability in response to both drugs. APY-0201 was considered the more potent PIKfyve inhibitor, with 71% of the samples exhibiting sensitivity in the nanomolar range (median EC 50 179 nM). We then devised a novel fused triazolo-pyrimidine chemical matter, PIK-001, which builds on known structures and which is confirmed to also selectively inhibit PIKfyve with high potency. PIK-001 was shown to be an effective IL12/23 inhibitor, non-toxic to normal peripheral blood mononuclear cells and exhibits broad activity in B cell malignancy cell lines (Figure) but exhibits selectivity, in that solid tumors (breast, pancreas, renal, cholangio) are much less sensitive or entirely resistant. As with other Pikfyve inhibitors PIK-001 disrupts lysosomal function and, consequently, autophagic flux in B cell malignancy. Autophagy is critical in plasma cells for sustainable immunoglobulin synthesis and endoplasmic reticulum capacity. This high basal necessity of autophagy in antibody producing plasma cells and MM cells indicate the clinical potential of this novel target. After in