Summary assay for small molecule Inhibitors of CXCR6
Prostate cancer (PCa) is the second leading cause of cancer death in American men and its morbidity has increased globally in recent years. The high mortality rate is closely associated with the spread of malignant cells to various tissues including bone. Nearly 10% of patients whose conditions are diagnosed as PCa initially present with bone metastasis and almost all patients who die of prostate more ..
Data Source: Sanford-Burnham Center for Chemical Genomics (SBCCG)
Source Affiliation: Sanford-Burnham Medical Research Institute (SBMRI, San Diego, CA)
Network: NIH Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Number: 1R03MH095589-01 (Cycle 18)
Assay Provider: Gregory Roth Ph.D., Sanford Burnham Medical Research Institute.
Prostate cancer (PCa) is the second leading cause of cancer death in American men and its morbidity has increased globally in recent years. The high mortality rate is closely associated with the spread of malignant cells to various tissues including bone. Nearly 10% of patients whose conditions are diagnosed as PCa initially present with bone metastasis and almost all patients who die of prostate cancers have skeletal involvement. Identifying new mechanisms that control bone metastasis is of great consequence to facilitate the design of therapeutics aimed at decreasing metastatic risk and/or its complications. To address this unmet medical need, our team is actively engaged in exploring the chemical biology, medicinal chemistry, and therapeutic significance of modulating tumor cell trafficking and metastasis via chemokine receptor inhibition. The primary objective of this proposal is to use high throughput screening methods to identify small molecule antagonist probes that selectively inhibit CXCR6. Our team intends to address a key hypothesis: The CXCR6/CXCL16 axis significantly contributes to PCa cell metastasis and subsequent bone invasion. A small molecule antagonist would block cancer cell trafficking; hence mediate a metastatic event and disease progression to bone. Thus, access to pharmacologically available small molecule antagonists will ultimately enable our studies in disease relevant models and allow for a more seamless translational advance to clinical applications.
Hu, W; Zhen, X; Xiong, B; Wang, B; Zhang, W; Zhou, W CXCR6 is expressed in human prostate cancer in vivo and is involved in the in vitro invasion of PC3 and LNCap cells. Cancer Sci 2008, 99, 1362-1369.
Matloubian, M; David, A; Engel, S; Ryan, JE; Cyster, JG A transmembrane CXC chemokine is a ligand for HIV-coreceptor Bonzo. Nature Immunol 2000, 1, 298-304.
Chandrasekar B, Bysani S, Mummidi S. CXCL16 signals via Gi, phosphatidylinositol 3-kinase, Akt, I kappa B kinase, and nuclear factor-kappa B and induces cell-cell adhesion and aortic smooth muscle cell proliferation. J Biol Chem 2004, 279, 3188-3196.
Probe molecules are defined as the positives of this assay and assigned a score of 100. Testing has not progressed to the point where a probe molecule has been identified.
Categorized Comment - additional comments and annotations
From MLP Probe Report:
Probe count: 2
MLP Probe ML# for probe 1: ML339
PubChem Substance ID (SID) for probe 1: 150864418
PubChem Compound ID (CID) for probe 1: 60202254
Probe type for probe 1: Antagonist
IC50/EC50 (nM) for probe 1: 140
Target for probe 1: hCXCR6 (gi: 5730106)
Disease relevance for probe 1: Cancer
Anti-target for probe 1: CCR6
Fold selectivity for probe 1: 560
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK158948/ (ID: 3054230)
Grant number for probe 1: MH095589
MLP Probe ML# for probe 2: ML358
PubChem Substance ID (SID) for probe 2: 161004951
PubChem Compound ID (CID) for probe 2: 70789776
Probe type for probe 2: Inhibitor
IC50/EC50 (nM) for probe 2: 240 +/- 80
Target for probe 2: SKN-1 pathway Pgst-4 (gi: 5730106)
Disease relevance for probe 2: Anthelmintic resistance
Anti-target for probe 2: C. elegans cytotoxicity Pgst-4
Fold selectivity for probe 2: > 267-fold
Grant number for probe 2: 1R21NS067678-01
NCBI Book chapter title for probe 1: Probing the CXCR6/CXCL16 Axis: Targeting Prevention of Prostate Cancer Metastasis