Synthesis and biological evaluation of novel purinyl quinazolinone derivatives as PI3Kδ-specific inhibitors for the treatment of hematologic malignancies. (1st September 2021)

• Record Type: Journal Article
• Authors: Kim, Yeon Su; Cheon, Min Gyeong; Boggu, Pulla Reddy; Koh, Su Youn; Park, Gi Min; Kim, Gahee; Park, Seo Hyun; Park, Sung Lyea; Lee, Chi Woo; Kim, Jong Woo; Jung, Young Hoon
• Is Part Of: Bioorganic & medicinal chemistry. Volume 45(2021)
• Publication Date: 2021-09-01
• Subjects: Quinazolinone -- PI3Kδ inhibitor -- Hematologic malignancies; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2021.116312
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: 15 novel purinyl quinazolinone derivatives were synthesized as PI3Kδ-specific inhibitors for the treatment of hematologic malignancies. Quinazolinone derivatives of the cyclopropyl group (in position of R 2 ) showed excellent PI3Kδ enzyme activity and selectivity for PI3Kδ/γ. Compound 6f could be a good candidate to treat Hematologic Malignancies. Abstract: Phosphatidylinositol 3-kinases (PI3Ks) mediate intracellular signal transduction. Aberrant PI3K signaling is associated with oncogenesis and disease progression in solid tumors and hematologic malignancies. Idelalisib (1 ), a first-in-class PI3Kδ inhibitor for the treatment of hematologic malignancies, was developed, but its sales were limited by black box warnings due to unexpected adverse effects. Therefore, to overcome these adverse events, various quinazolinone derivatives were synthesized and evaluated in vitro based on their inhibitory activity against the PI3K enzyme and the viability of cell lines such as MOLT and SUDHL. Among them, 6f (IC50 = 0.39 nM) and 6m (IC50 = 0.09 nM) showed excellent enzyme activity, and 6m displayed an approximately four-fold higher selectivity for PI3Kγ/δ compared with Idelalisib (1 ). Furthermore, in vivo PK experiments with 6f and 6m revealed that 6f (AUClast = 81.04 h*ng/mL, Cmax = 18.34 ng/mL, Tmax = 0.5 h, t1/2 = 10.2 h in 1 mpk dose) had improved PK compared with 1 . Finally, further experiments will be conducted with 6f selected as a candidate, and the potential for it to be developed as a treatment with good efficacy for hematologic malignancies will be determined.