Discovery of novel KRAS‒PDEδ inhibitors with potent activity in patient-derived human pancreatic tumor xenograft models.
10.1016/j.apsb.2021.07.009
- Author:
Long CHEN
1
;
Jing ZHANG
2
;
Xinjing WANG
3
;
Yu LI
1
;
Lu ZHOU
4
;
Xiongxiong LU
3
;
Guoqiang DONG
1
;
Chunquan SHENG
1
Author Information
1. School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
2. Department of Pathology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
3. Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai 200025, China.
4. Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
- Publication Type:Journal Article
- Keywords:
Anti-pancreatic cancer activity;
KRAS‒PDEδ interaction;
Lead optimization;
PDX;
SBDD;
Spiro-cyclic inhibitors
- From:
Acta Pharmaceutica Sinica B
2022;12(1):274-290
- CountryChina
- Language:English
-
Abstract:
KRAS‒PDEδ interaction is revealed as a promising target for suppressing the function of mutant KRAS. The bottleneck in clinical development of PDEδ inhibitors is the poor antitumor activity of known chemotypes. Here, we identified novel spiro-cyclic PDEδ inhibitors with potent antitumor activity both in vitro and in vivo. In particular, compound 36l (K D = 127 ± 16 nmol/L) effectively bound to PDEδ and interfered with KRAS-PDEδ interaction. It influenced the distribution of KRAS in Mia PaCa-2 cells, downregulated the phosphorylation of t-ERK and t-AKT and promoted apoptosis of the cells. The novel inhibitor 36l exhibited significant in vivo antitumor potency in pancreatic cancer patient-derived xenograft (PDX) models. It represents a promising lead compound for investigating the druggability of KRAS‒PDEδ interaction.
