Design, synthesis, and biological evaluation of structurally modified isoindolinone and quinazolinone derivatives as hedgehog pathway inhibitors.
The Hedgehog (Hh) signaling pathway is associated with diverse aspects of cellular events, such as cell migration, proliferation, and differentiation throughout embryonic development and tissue patterning. An abnormal Hh signaling pathway is linked to numerous human cancers, including basal cell carcinoma (BCC), medulloblastoma (MB), lung cancer, prostate cancer, and ovarian cancer, and it is therefore a promising target in cancer therapy. Using a structure-hopping approach, we designed new Hh signaling pathway inhibitors with isoindolinone or quinazolinone moieties, which were synthesized and biologically evaluated using an 8xGli-luciferase (Gli-Luc) reporter assay in NIH3T3 cells. Compounds 9-11 and 14 with isoindolinone scaffolds demonstrated moderate Hh inhibitory activity; whereas quinazolinone derivatives 24, 29, 32, 34, and 35 exhibited good potency with submicromolar IC50values and the analog 28 showed nanomolar IC50value. Although sonidegib shows a decrease in inhibitory effect on vismodegib resistance-conferring Smo mutants, the structurally modified new compounds not only possess the pharmacophoric properties of Hh pathway inhibition but also preserve the suppressive potency in drug-resistant Smo mutants. Mechanistically, quinazolinone derivatives 28 and 34 suppress Hh signaling by blocking Smo and Gli translocation into the cilia, similar to vismodegib and sonidegib. Additionally, the human microsomal stability of the representative analogs 28 and 34 were determined to be comparable to that of the reference compound sonidegib. Thus, these new scaffolds can serve as a platform for the development of novel cancer therapeutics targeting the Hh pathway.
BK21Plus R-FIND Team, College of Pharmacy, Dongguk University-Seoul, 32 Dongguk-ro, Ilsandong-gu, Goyang, 410-820, Republic of Korea.
Deepak
D
Bhattarai
College of Pharmacy, Dongguk University, 32 Dongguk-ro, Ilsandong-gu, Goyang, 410-820, Republic of Korea.
Joo Hyun
JH
Jung
BK21Plus R-FIND Team, College of Pharmacy, Dongguk University-Seoul, 32 Dongguk-ro, Ilsandong-gu, Goyang, 410-820, Republic of Korea.
Seunghyeon
S
Han
College of Pharmacy, Dongguk University, 32 Dongguk-ro, Ilsandong-gu, Goyang, 410-820, Republic of Korea.
Hankyu
H
Lee
Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungbuk 363-883, Republic of Korea.
Soo Jin
SJ
Oh
College of Pharmacy, Dongguk University, 32 Dongguk-ro, Ilsandong-gu, Goyang, 410-820, Republic of Korea. Electronic address: kohw@dongguk.edu.
Hyuk Wan
HW
Ko
BK21Plus R-FIND Team, College of Pharmacy, Dongguk University-Seoul, 32 Dongguk-ro, Ilsandong-gu, Goyang, 410-820, Republic of Korea. Electronic address: Kaylee@dongguk.edu.
Kyeong
K
Lee
D000818:Animals; D015195:Drug Design; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D054833:Isoindoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D041681:NIH 3T3 Cells; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
D053823:Hedgehog Proteins; C110621:Isoindol-1-one; D054833:Isoindoles; D052999:Quinazolinones
Gli; Hedgehog pathway; Isoindolinone; Quinazolinone; Smoothened; Structure hopping