Discovery, Optimization, and Evaluation of Potent and Selective PI3Kδ‑γ Dual Inhibitors for the Treatment of B‑cell Malignancies

Nowadays, PI3Kδ-γ dual inhibitors have been
approved
for the treatment of B-cell malignancies. Dual inhibition of PI3Kδ
and PI3Kγ represents a unique therapeutic opportunity and may
confer greater benefits than either isoform inhibition alone in the
management of hematological malignancies. However, currently available
dual inhibitors of PI3Kδ-γ compromise in at least one
of several essential properties in terms of potency, selectivity,
and pharmacokinetic (PK) profiles. Hence, the main challenge of our
optimization campaign was to identify an oral available PI3Kδ-γ
dual inhibitor with an optimum balance of potency, selectivity, and
PK profiles. The medicinal chemistry efforts culminated in the discovery
of compound 58, which exhibited strong potency and high
selectivity along with excellent in vivo profiles
as demonstrated through PK studies in rats and through pharmacodynamic
studies in an SUDHL-6 xenograft model. All the results suggest that
compound 58 may be a promising candidate for the treatment
of B-cell malignancies.