Design, synthesis, and biological evaluation of structurally modified isoindolinone and quinazolinone derivatives as hedgehog pathway inhibitors

Deepak Bhattarai, Joo Hyun Jung, Seunghyeon Han, Hankyu Lee, Soo Jin Oh, Hyuk Wan Ko, Kyeong Lee

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1036-1050
Number of pages15
JournalEuropean Journal of Medicinal Chemistry
Volume125
DOIs
Publication statusPublished - 2017 Jan 1

Fingerprint

Quinazolinones
HhAntag691
Derivatives
Prostatic Neoplasms
Scaffolds
Neoplasms
Medulloblastoma
Cilia
Basal Cell Carcinoma
Luciferases
Ovarian Neoplasms
Embryonic Development
Cell Movement
Cell Differentiation
Lung Neoplasms
Cell Proliferation
Assays
Cells
Therapeutics
Tissue

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Bhattarai, Deepak ; Jung, Joo Hyun ; Han, Seunghyeon ; Lee, Hankyu ; Oh, Soo Jin ; Ko, Hyuk Wan ; Lee, Kyeong. / Design, synthesis, and biological evaluation of structurally modified isoindolinone and quinazolinone derivatives as hedgehog pathway inhibitors. In: European Journal of Medicinal Chemistry. 2017 ; Vol. 125. pp. 1036-1050.
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Design, synthesis, and biological evaluation of structurally modified isoindolinone and quinazolinone derivatives as hedgehog pathway inhibitors. / Bhattarai, Deepak; Jung, Joo Hyun; Han, Seunghyeon; Lee, Hankyu; Oh, Soo Jin; Ko, Hyuk Wan; Lee, Kyeong.

In: European Journal of Medicinal Chemistry, Vol. 125, 01.01.2017, p. 1036-1050.

Research output: Contribution to journalArticle

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AU - Bhattarai, Deepak

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AU - Oh, Soo Jin

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