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

Abstract

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.

• Authors: Kongjun Liu, Wei Zheng, Yong Chen, Minghai Tang, Dan Li, Dexin Deng, Tao Yang, Chufeng Zhang, Jiang Liu, Xue Yuan, Mingsong Shi, Xiandeng Li, Yong Guo, Yanting Zhou, Min Zhao, Lijuan Chen
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 14 Pg. 9893-9917 (07 28 2022) ISSN: 1520-4804 [Electronic] United States
• PMID: 35831917 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Class I Phosphatidylinositol 3-Kinases

Topics

• Animals
• B-Lymphocytes
• Class I Phosphatidylinositol 3-Kinases
• Humans
• Neoplasms
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (chemistry, pharmacology, therapeutic use)
• Rats