Discovery of small molecule drug candidates that disrupt the NEMO/IKK signaling c

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$299,307.00
Award Year:
2010
Program:
SBIR
Phase:
Phase I
Contract:
1R43CA153676-01
Award Id:
95936
Agency Tracking Number:
CA153676
Solicitation Year:
n/a
Solicitation Topic Code:
NCI
Solicitation Number:
n/a
Small Business Information
CARMOT THERAPEUTICS, INC., 100 SAINT ALBANS RD, BERKELEY, CA, 94708
Hubzone Owned:
N
Minority Owned:
N
Woman Owned:
N
Duns:
828863022
Principal Investigator:
STIG HANSEN
() -
Business Contact:
STIG HANSEN
() -
Research Institution:
n/a
Abstract
DESCRIPTION (provided by applicant): Protein-protein interactions represent the largest untapped opportunity for therapeutic development. The number of protein-protein interactions in human cells has been estimated to exceed 100,000, well above the ~30,000 human genes. This multitude of protein-protein interactions constitutes a tremendous opportunity for therapeutic innovation as the field has languished due to lack of promising technological approaches. To address the shortcomings in existing technologie s, Carmot is developing an innovative lead finding technology called Chemotype Evolution. Chemotype Evolution is a proprietary technology based on the well- validated approach of making and screening target-directed compound libraries, but uses fragment-ba sed concepts to take this approach to a new level. Chemotype Evolution enables an evolutionary screening paradigm that is unprecedented in small molecule drug discovery and provides rapid and inexpensive access to novel and target-relevant chemical diversi ty that is not easily accessed by other technologies. The long-term objective of this proposal is to develop small molecule drugs that stimulate tumor cell apoptosis and inhibit inflammatory signaling in the tumor environment. The NF-kB pathway is a key s ignaling node in the communication between tumors and the inflammatory microenvironment. The activities of anticancer drugs bortezomib and thalidomide have in part been attributed to indirect inhibition of NF-kB. Despite intensive efforts, viable drug-lead s that directly target NF-kB activation have not been identified. The protein-protein interaction between IkB Kinase (IKK) and Nf-kB Essential Modulator (NEMO), referred to as NEMO/IKK, has emerged as a promising target for inhibiting NF-kB activation: Pep tides that encompass the NEMO binding domain (NBD) of IKK can block IKK binding to NEMO and inhibit NF-kB activation in vivo. The specific objective of this Phase I proposal is to discover drug-like inhibitors of NF-kB activation. To achieve this, Carmot will use Chemotype Evolution to evolve NBD peptides into small molecule inhibitors of NEMO/IKK. In the first aim, Chemotype Evolution will be used to discover hybrid molecules of NBD peptides and drug fragments that bind to NEMO. In the second aim, Chemoty pe Evolution will be used to evolve these hybrids into drug-like inhibitors of IKK binding to NEMO. In the third aim, the best inhibitors will be characterized in more detail to lay the foundation for a Phase II proposal to advance select inhibitors toward s drug candidates for treating human cancers. The proposed research will validate Chemotype Evolution as a transformative technology for targeting protein-protein interactions and has high potential both for scientific innovation and for development or pr oducts that have significant economic and societal benefits. PUBLIC HEALTH RELEVANCE: Localized inflammation plays an essential role in the progression of human cancer and is a promising target for therapeutic intervention. This proposal offers an i nnovative strategy for targeting inflammation in tumor tissue. The objective is to identify lead compounds with the potential to become drug candidates for treating human cancers.

* information listed above is at the time of submission.

Agency Micro-sites


SBA logo

Department of Agriculture logo

Department of Commerce logo

Department of Defense logo

Department of Education logo

Department of Energy logo

Department of Health and Human Services logo

Department of Homeland Security logo

Department of Transportation logo

Enviromental Protection Agency logo

National Aeronautics and Space Administration logo

National Science Foundation logo
US Flag An Official Website of the United States Government