Development of hedgehog pathway inhibitors by epigenetically targeting GLI through BET bromodomain for the treatment of medulloblastoma

Autor: Wenfu Tan, Huaqian Ding, Xiaohua Liu, Chunyong Ding, Juan Wang, Yalei Li, Ao Zhang, Yu Zhang, Hongchun Liu, Wenjing Huang
Rok vydání: 2021
Předmět:
SAR
structure−activity relationship
Hedgehog signaling pathway
BRD4
p.o.
per os
medicine.medical_treatment
WNT
wingless
PK
pharmacokinetic
Targeted therapy
BRD4
bromodomain-containing protein 4
03 medical and health sciences
0302 clinical medicine
medicine
General Pharmacology
Toxicology and Pharmaceutics
BET
bromo and extra C-terminal bromodomain proteins
Hedgehog
BCC
basal cell carcinoma
030304 developmental biology
Medulloblastoma
0303 health sciences
MB
medulloblastoma
TGI
tumor growth inhibition
Oncogene
SHH
Sonic hedgehog
Chemistry
lcsh:RM1-950
medicine.disease
HH
hedgehog
Bromodomain
lcsh:Therapeutics. Pharmacology
Drug resistance
030220 oncology & carcinogenesis
PTCH
patched
Cancer research
Original Article
i.v.
intravenous injection
Smoothened
HTRF
homogeneous time-resolved fluorescence
hERG
human ether-a-go-go-related gene
SMO
smoothened
GLI
Zdroj: Acta Pharmaceutica Sinica B, Vol 11, Iss 2, Pp 488-504 (2021)
Acta Pharmaceutica Sinica. B
ISSN: 2211-3835
DOI: 10.1016/j.apsb.2020.07.007
Popis: Medulloblastoma (MB) is a common yet highly heterogeneous childhood malignant brain tumor, however, clinically effective molecular targeted therapy is lacking. Modulation of hedgehog (HH) signaling by epigenetically targeting the transcriptional factors GLI through bromodomain-containing protein 4 (BRD4) has recently spurred new interest as potential treatment of HH-driven MB. Through screening of current clinical BRD4 inhibitors for their inhibitory potency against glioma-associated oncogene homolog (GLI) protein, the BRD4 inhibitor 2 was selected as the lead for further structural optimization, which led to the identification of compounds 25 and 35 as the high potency HH inhibitors. Mechanism profiling showed that both compounds suppressed HH signaling by interacting with the transcriptional factor GLI, and were equally potent against the clinical resistant mutants and the wild type of smoothened (SMO) receptor with IC50 values around 1 nmol/L. In the resistant MB allograft mice, compound 25 was well tolerated and markedly suppressed tumor growth at both 5 mg/kg (TGI = 83.3%) and 10 mg/kg (TGI = 87.6%) doses. Although further modification is needed to improve the pharmacokinetic (PK) parameters, compound 25 represents an efficacious lead compound of GLI inhibitors, possessing optimal safety and tolerance to fight against HH-driven MB.
Graphical abstract A systemic structure and hedgehog activity relationship study was conducted based on clinical BRD4 inhibitor ABBV-075. Compound 25 represents a new high potency hedgehog (HH) inhibitor both in vitro and in vivo, possessing optimal safety and tolerance to fight against HH-driven MB.Image 1
Databáze: OpenAIRE
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