Abstract
Human farnesyl pyrophosphate synthase (Homo sapiens FPPS, HsFPPS) is a target for treating bone resorption diseases and some cancers. HsFPPS is potently inhibited by bisphosphonates, but due to poor cell penetration and distribution in soft tissue, there is currently interest in the development of non-bisphosphonate inhibitors as cancer therapeutics. Here, we report the discovery and development of HsFPPS inhibitors based on the phenolic diterpene carnosic acid (CA), an antimicrobial found in rosemary and sage, which showed better cellular anticancer activities than the bisphosphonate drug zoledronate in pancreatic cancer cell lines, as well as an HsFPPS-dependent mechanism of action. Hit-to-lead optimization of CA improved HsFPPS inhibition by >100-fold. A slow dissociation inhibition pattern and a noncompetitive allosteric binding mode were found, and cellular mechanism-of-action studies showed that these inhibitors inhibit tumor cell growth primarily by inhibiting HsFPPS, leading to downregulation of Ras prenylation and cell apoptosis. The discovery of this series of compounds together with proof-of-mechanism in pancreatic cancer cells may pave the way for targeting HsFPPS in soft tissue cancers using natural-product-derived inhibitors.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 10867-10896 |
| Number of pages | 30 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 62 |
| Issue number | 23 |
| DOIs | |
| State | Published - Dec 12 2019 |
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ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
Cite this
Farnesyl Pyrophosphate Synthase as a Target for Drug Development : Discovery of Natural-Product-Derived Inhibitors and Their Activity in Pancreatic Cancer Cells. / Han, Shuai; Li, Xin; Xia, Yun; Yu, Zhengsen; Cai, Ningning; Malwal, Satish R.; Han, Xu; Oldfield, Eric; Zhang, Yonghui.
In: Journal of Medicinal Chemistry, Vol. 62, No. 23, 12.12.2019, p. 10867-10896.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Farnesyl Pyrophosphate Synthase as a Target for Drug Development
T2 - Discovery of Natural-Product-Derived Inhibitors and Their Activity in Pancreatic Cancer Cells
AU - Han, Shuai
AU - Li, Xin
AU - Xia, Yun
AU - Yu, Zhengsen
AU - Cai, Ningning
AU - Malwal, Satish R.
AU - Han, Xu
AU - Oldfield, Eric
AU - Zhang, Yonghui
PY - 2019/12/12
Y1 - 2019/12/12
N2 - Human farnesyl pyrophosphate synthase (Homo sapiens FPPS, HsFPPS) is a target for treating bone resorption diseases and some cancers. HsFPPS is potently inhibited by bisphosphonates, but due to poor cell penetration and distribution in soft tissue, there is currently interest in the development of non-bisphosphonate inhibitors as cancer therapeutics. Here, we report the discovery and development of HsFPPS inhibitors based on the phenolic diterpene carnosic acid (CA), an antimicrobial found in rosemary and sage, which showed better cellular anticancer activities than the bisphosphonate drug zoledronate in pancreatic cancer cell lines, as well as an HsFPPS-dependent mechanism of action. Hit-to-lead optimization of CA improved HsFPPS inhibition by >100-fold. A slow dissociation inhibition pattern and a noncompetitive allosteric binding mode were found, and cellular mechanism-of-action studies showed that these inhibitors inhibit tumor cell growth primarily by inhibiting HsFPPS, leading to downregulation of Ras prenylation and cell apoptosis. The discovery of this series of compounds together with proof-of-mechanism in pancreatic cancer cells may pave the way for targeting HsFPPS in soft tissue cancers using natural-product-derived inhibitors.
AB - Human farnesyl pyrophosphate synthase (Homo sapiens FPPS, HsFPPS) is a target for treating bone resorption diseases and some cancers. HsFPPS is potently inhibited by bisphosphonates, but due to poor cell penetration and distribution in soft tissue, there is currently interest in the development of non-bisphosphonate inhibitors as cancer therapeutics. Here, we report the discovery and development of HsFPPS inhibitors based on the phenolic diterpene carnosic acid (CA), an antimicrobial found in rosemary and sage, which showed better cellular anticancer activities than the bisphosphonate drug zoledronate in pancreatic cancer cell lines, as well as an HsFPPS-dependent mechanism of action. Hit-to-lead optimization of CA improved HsFPPS inhibition by >100-fold. A slow dissociation inhibition pattern and a noncompetitive allosteric binding mode were found, and cellular mechanism-of-action studies showed that these inhibitors inhibit tumor cell growth primarily by inhibiting HsFPPS, leading to downregulation of Ras prenylation and cell apoptosis. The discovery of this series of compounds together with proof-of-mechanism in pancreatic cancer cells may pave the way for targeting HsFPPS in soft tissue cancers using natural-product-derived inhibitors.
UR - http://www.scopus.com/inward/record.url?scp=85076242884&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85076242884&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.9b01405
DO - 10.1021/acs.jmedchem.9b01405
M3 - Article
C2 - 31725297
AN - SCOPUS:85076242884
VL - 62
SP - 10867
EP - 10896
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 23
ER -