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A High Throughput Assay to Identify Drug Candidates Targeting Protein Kinase A in Non-ATP Binding Sites

技術優勢

Identification of non-ATP-competitive ligands. Ability to selectively target only the disease associated isoforms of PKA. Screening of compounds that modulate PKA function through stabilizing active or inactive conformational states. Identification of both agonists and antagonists of PKA with fluorescence polarization as readout. Fluorescently-labeled peptide probe binds to the substrate binding site of PKA.

技術應用

Identification of compounds for the treatment of various PKA mediated conditions, including several cancers (e.g. carney complex, pituitary, breast cancer) and diseases of the immune system (Systemic lupus erythematosus (SLE) and HIV).

詳細技術說明

UC San Diego researchers have developed a novel high-throughput screening assay to identify drug candidates that specifically target protein kinase A. The technique is based on fluorescence polarization of a competitive peptide probe, allowing the screening of compounds that activate or inhibit the catalytic function of the kinase. The assay is therefore designed to mask the ATP binding site such that the compounds discovered are not ATP competitive. Moreover, the method can be used with any of the four isoforms of the kinase regulatory subunit, allowing the potential identification of small molecules that selectively target the disease associated isoforms of PKA.

*Abstract

The cAMP-dependent protein kinase A (PKA) is a serine/threonine protein kinase implicated in several cancers. PKA is also suggested to be a therapeutic target for immune system diseases. However, given the ubiquitous nature of this kinase, targeting the ATP-binding site of the catalytic subunit with an ATP-competitive inhibitor would just as likely kill healthy cells. Current high throughput screening assays are more likely to identify strong binding ATP-competitors than non-ATP competitive compounds. Therefore, there is a need for an assay system to discern true small molecule agonist and antagonists from ATP competitors.

*IP Issue Date

Feb 22, 2011

*Principal Investigation

Name: Sanjay Saldanha

Department:

Name: Susan Taylor

Department:

附加資料

Patent Number: US7892776B2
Application Number: US2008151318A
Inventor: Taylor, Susan S. | Saldanha, Sanjay A.
Priority Date: 4 May 2007
Priority Number: US7892776B2
Application Date: 5 May 2008
Publication Date: 22 Feb 2011
IPC Current: C12Q000146
US Class: 435015 | 43500618 | 5360232 | 435006
Assignee Applicant: The Regents of the University of California
Title: Screening assay to identify modulators of protein kinase A
Usefulness: Screening assay to identify modulators of protein kinase A
Summary: The method is useful for screening compounds that modulate an activity of protein kinase A (claimed). It is also useful for screening agonists and antagonists of PKA holoenzyme; for treating, preventing, and ameliorating various PKA-mediated conditions, including but not limited to several cancers and diseases of the immune system, where the diseases include cancers including but not limited to solid tumors (e.g. breast cancer), T cell response to HIV infection that are responsive to inhibitors of cAMP activation; systemic lupus erythematosus autoimmune disease and lymphoma, where the cancers include cancers of the brain (gliomas), breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, or thyroid; and for prevention, treatment, or amelioration of RAF kinase, including v-raf viral oncogene susceptibility protein (BRAF) kinase, mediated diseases or its symptoms.
Novelty: Screening compounds that modulate protein kinase A comprises contacting test compound with a mixture comprising a fluorescently-labeled peptide probe, a cyclic nucleotide or its analog, a C-subunit and an R-subunit of protein kinase A

主要類別

診斷/治療

細分類別

人類免疫缺陷病毒

申請號碼

7892776

其他

State Of Development

This technology is offered exclusively or nonexclusively in the U.S. and/or worldwide territories.

Related Materials

1. Saldanha SA, Kaler G, Cottam HB, Abagyan R, Taylor SS. Assay principle for modulators of protein-protein interactions and its application to non-ATP-competitive ligands targeting protein kinase A. Anal Chem. 78(24):8265-72 (2006).
2. Susan Taylor, Ph.D., is a professor in the Department of Chemistry and Biochemistry and the Department of Pharmacology at UC San Diego. Visit http://susantaylorlab.ucsd.edu for more information about this inventor.

Tech ID/UC Case

19537/2006-160-0

Related Cases

2006-160-0

國家/地區

美國