PIK-001: A Promising Pikfyve Inhibitor Targeting Multiple Myeloma

A study was conducted to explore the effects of certain drugs on plasma cell biology, focusing on multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL) cell lines. The research involved screening with a variety of FDA-approved oncology drugs, kinase inhibitors, and epigenetic compounds. Among these, APY-0201 and its related drug, apilimod, were identified as primary inhibitors of the PikFyve enzyme. These drugs were initially designed to suppress the production of interleukin-12 and interleukin-23 but were later found to have a significant impact on cellular viability in MM cell lines.

The study showed that APY-0201 reduced the viability of MM cell lines in a dose-dependent manner, with a median effective concentration (EC50) of 55 nanomolar and a maximum inhibition rate of 81%. In ex vivo primary samples, 40% showed sensitivity to APY-0201 within 24 hours, and 47% had an EC50 below 100 nanomolar. After a 72-hour incubation, 90% of the samples exhibited a dose-dependent response to both APY-0201 and apilimod, with APY-0201 being more potent.

A new chemical compound, PIK-001, was developed, which selectively inhibits PikFyve with high potency and acts as an IL12/23 inhibitor. It was found to be non-toxic to normal blood cells and showed broad activity against B cell malignancies, while solid tumors were less sensitive or resistant. PIK-001 disrupts lysosomal function and autophagic flux, which is crucial for plasma cells, indicating its potential as a therapeutic target.

In preliminary animal studies, PIK-001 was administered orally to mice with transgenic MM tumors. The treatment significantly reduced tumor growth and increased survival rates compared to untreated controls. The compound was well-tolerated and effective in preventing myeloma growth, suggesting its potential for future clinical trials.