Deciphering the Potential of PWT143: A PI3K Delta Inhibitor in Hematologic Malignancies

Initial trials of small molecule inhibitors targeting kinases in the B Cell Receptor pathway have shown positive results in treating B cell cancers. Notable kinases are PI3K delta, BTK, and SYK, with GS-1101, ibrutinib, and fostamatinib being their respective inhibitors. These have been effective in diseases such as CLL, NHL, MCL, and DLBCL. PI3K delta is also expressed in various immune cells and is involved in signals from different immunoreceptors, suggesting that its inhibitors could be beneficial for a range of hematological cancers.

PWT143, a selective PI3K delta inhibitor, has been identified as a promising candidate for development. It has demonstrated high potency against PI3K delta in cellular assays and has shown selectivity over other isoforms and kinases. In a functional assay, it also displayed promising results.

When tested against a panel of 12 human hematological cancer cell lines, PWT143 showed lower IC50 values compared to other inhibitors, indicating its effectiveness. It also performed well in assays with patient-derived peripheral blood cells, particularly in CLL and AML cases, where it showed significantly lower IC50 values than GS-1101 or ibrutinib.

The activity of GS-1101 and ibrutinib is primarily through inhibiting BCR signaling that maintains tumor cells in the lymph node, leading to lymphocytosis as a side effect. In contrast, PWT143's direct impact on tumor cell viability, along with its mechanism of action, suggests it may have enhanced clinical efficacy.

The preclinical data for PWT143 highlight its potential as a strong and selective PI3K delta inhibitor, making it a compelling option for further clinical development. Several individuals associated with the study have disclosed affiliations and financial interests with Pathway Therapeutics, indicating a potential conflict of interest.