TY - JOUR
T1 - Scaffold repurposing of fendiline
T2 - Identification of potent KRAS plasma membrane localization inhibitors
AU - Wang, Pingyuan
AU - van der Hoeven, Dharini
AU - Ye, Na
AU - Chen, Haiying
AU - Liu, Zhiqing
AU - Ma, Xiaoping
AU - Montufar-Solis, Dina
AU - Rehl, Kristen M.
AU - Cho, Kwang Jin
AU - Thapa, Sabita
AU - Chen, Wei
AU - van der Hoeven, Ransome
AU - Frost, Jeffrey A.
AU - Hancock, John F.
AU - Zhou, Jia
N1 - Publisher Copyright:
© 2021 Elsevier Masson SAS
PY - 2021/5/5
Y1 - 2021/5/5
N2 - KRAS plays an essential role in regulating cell proliferation, differentiation, migration and survival. Mutated KRAS is a major driver of malignant transformation in multiple human cancers. We showed previously that fendiline (6) is an effective inhibitor of KRAS plasma membrane (PM) localization and function. In this study, we designed, synthesized and evaluated a series of new fendiline analogs to optimize its drug properties. Systemic structure-activity relationship studies by scaffold repurposing led to the discovery of several more active KRAS PM localization inhibitors such as compounds 12f (NY0244), 12h (NY0331) and 22 (NY0335) which exhibit nanomolar potencies. These compounds inhibited oncogenic KRAS-driven cancer cell proliferation at single-digit micromolar concentrations in vitro. In vivo studies in a xenograft model of pancreatic cancer revealed that 12h and 22 suppressed oncogenic KRAS-expressing MiaPaCa-2 tumor growth at a low dose range of 1–5 mg/kg with no vasodilatory effects, indicating their potential as chemical probes and anticancer therapeutics.
AB - KRAS plays an essential role in regulating cell proliferation, differentiation, migration and survival. Mutated KRAS is a major driver of malignant transformation in multiple human cancers. We showed previously that fendiline (6) is an effective inhibitor of KRAS plasma membrane (PM) localization and function. In this study, we designed, synthesized and evaluated a series of new fendiline analogs to optimize its drug properties. Systemic structure-activity relationship studies by scaffold repurposing led to the discovery of several more active KRAS PM localization inhibitors such as compounds 12f (NY0244), 12h (NY0331) and 22 (NY0335) which exhibit nanomolar potencies. These compounds inhibited oncogenic KRAS-driven cancer cell proliferation at single-digit micromolar concentrations in vitro. In vivo studies in a xenograft model of pancreatic cancer revealed that 12h and 22 suppressed oncogenic KRAS-expressing MiaPaCa-2 tumor growth at a low dose range of 1–5 mg/kg with no vasodilatory effects, indicating their potential as chemical probes and anticancer therapeutics.
KW - Fendiline
KW - KRAS
KW - Pancreatic cancer
KW - Plasma membrane localization
KW - Scaffold repurposing
UR - http://www.scopus.com/inward/record.url?scp=85102829217&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85102829217&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2021.113381
DO - 10.1016/j.ejmech.2021.113381
M3 - Article
C2 - 33756124
AN - SCOPUS:85102829217
SN - 0223-5234
VL - 217
JO - European journal of medicinal chemistry
JF - European journal of medicinal chemistry
M1 - 113381
ER -