The Biology-Chemistry Centers were originally funded as program project grants (P01’s) in response to two RFA’s (CA-97-006 and CA-98-009). They supported multi-disciplinary research with an emphasis on new technologies in high throughput screening and combinatorial chemistry for cancer drug discovery. A total of 6 awards were made in response to the two RFA’s. Three of these grants were successfully renewed via the regular P01 (non-RFA) review process. These Centers have brought together innovative approaches to (a) the generation of structural diversity, such as combinatorial synthesis, parallel synthesis or genetic manipulation of biosynthetic pathways in producer organisms and (b) novel, smart assays directed at molecular events or targets important in the neoplastic process and thus suitable for cancer drug discovery.
Active Grants:
"Combinatorial Approaches for Novel Anticancer Agents" P01 CA078039
Dr. John Stephen Lazo, Principal Investigator University of Pittsburgh
Grant period: 5/15/1998 through 3/31/2010
Abstract: DESCRIPTION (provided by applicant): The overall goal of this revised renewal application for a Chemical-Biology Interface Program Project is to generate novel chemical libraries based on potent natural product-derived pharmacophores and to identify promising new lead structures that affect cancer-relevant molecular targets. In this translational application, we intend to exploit recent advances in solid phase and solution phase combinatorial chemistry developed in our laboratories to synthesize unique natural product-based, small-molecular libraries. Our synthetic efforts are focused on two highly relevant molecular targets for solid tumors: (a) microtubules/tubulin, which is an established critical target for several clinically active anticancer agents, including the taxanes and vinca alkaloids, and (b) dual specificity phosphatases that have been documented to be novel proto-oncogenes and regulators of cell cycle progression and apoptosis. In addition to in vitro biochemical assays, we propose to develop and employ novel cellular assays that will be applicable to a wide variety of cancer-related signal transduction and cell structural targets. A highly innovative dynamic combinatorial library approach will also be undertaken to probe new chemical structures and to provide a unique chemical platform for future compound generation. Enhancement and expansion of the fundamental bioisosteres will occur with the assistance of the Bioinformation and Cell-based Assay Core B, which will also maintain the central chemical and biological database. Our Preclinical Evaluation Core (Core C) will evaluate the pharmacodynamics and pharmacokinetics of prioritized compounds in relevant mouse models. Our overall hypothesis is that novel; structurally unique, lead antineoplastic agents can be generated and identified by an integrated use of contemporary combinatorial chemistry, biochemistry, pharmacology, cell biology and informatics.
"Combinatorial Chemistry and Cancer Targets" P01 CA078045
Dr. Peter K. Vogt, Principal Investigator The Scripps Research Institute
Grant period: 5/7/1998 through 2/28/2009
Abstract: DESCRIPTION (provided by applicant): The basic goal of this proposal is to combine the power of combinatorial chemistry with the modern knowledge of cancer biology and genetics in an effort to identify novel anticancer compounds. The program project consists of one chemistry and two biology projects and two cores. The first project (Boger) proposes the production and testing of libraries targeted to protein-protein and protein-DNA interactions. The libraries produced in the past funding period will be increased to 10[6] compounds and lead optimization will continue. Project two (Cheresh) deals with the isolation of angiogenesis inhibitors. It will develop inhibitors of matrix metalloproteinase 2, refine the nanoparticle genes delivery technology of the past funding period and test inhibitors of integrin alpha3beta1. Project 3 (Vogt) proposes the isolation of small molecule regulators of the Myc network and of beta-catenin-LEF interaction. It will also continue the identification and optimization of lead anticancer compounds through cellular and in vitro assays. The cores are for animal studies and instruments. The research projects are connected and interdependent. The interactions are mutual; the reiterative process of library and compound optimization rests on the interchange of chemical materials and of biological information. The collaborating groups of this Program Project have become an integrated unit that incorporates a wide range of expertise and interests and applies them to the common goal, new anticancer compounds.
"Probing Cell Division with Synthetic Chemistry" P01 CA078048
Dr. Timothy Mitchison, Principal Investigator Harvard Medical School
Grant period: 5/15/1998 through 4/30/2009
Abstract: DESCRIPTION (provided by applicant): Our goals are to develop "chemical genetics", an approach to solving mechanism in cell biology based on use of small molecule tools, and to discover small molecule tools that perturb cell division by novel mechanisms. The small molecules we discover will impact on cancer by revealing target protein/small molecule pairs as the starting point for anti-mitotic drug design. We will develop diversity-oriented synthesis (DOS) pathways that allow synthesis of large libraries of structurally diverse small molecules with complex stereochemistry. Library design will be guided by principles from cheminformatics to maximize diversity. We will screen these libraries for small molecules that perturb cell division, using automated fluorescence microscopy of treated cells, followed by computational analysis of images, to find hits that cause specific phenotypic effects. We will also screen for small molecules that inhibit the function of key proteins known to be involved in cell division using enzymatic assays and assays of protein binding to small molecules immobilized as microarrays. Library synthesis and screening will use a technology platform we developed in the previous funding period. We will optimize the affinity of interesting hits by synthesizing and screening "tuning" libraries that sample chemical space around the original hit. We will start by optimizing a hit we found from a DOS library that targets Eg5, a motor protein required for cell division. We will develop a new method for finding the protein targets of small molecules that cause interesting phenotypic effects, based on in vitro translation of cDNA libraries, and selection of the target protein by its binding to the small molecule immobilized on glass. Having found small molecule tools that perturb cell division by novel mechanisms, we will test their ability to kill cancer cells in vitro.
Archive Information:
Cancer Drug Discovery: Diversity Generation and Smart Assays, RFA CA-97-006, NIH Guide, May 9, 1997-Closed: 8/22/97 (four awards made) http://grants.nih.gov/grants/guide/rfa-files/rfa-ca-97-006.html
Cancer Drug Discovery: Diversity Generation and Smart Assays, RFA CA-98-009, NIH Guide, April 3, 1998-Closed: 11/18/98 (two awards made) http://grants.nih.gov/grants/guide/rfa-files/rfa-ca-98-009.html
Three of the original awards are listed below. The other three are listed above.
"Combinatorial Approaches to Treat Neoplastic Diseases" P01 CA078040
Dr. Richard A. Houghton, Principal Investigator Torrey Pines Institute for Molecular Studies
Grant period: 5/4/1998 through 6/30/2003
"Cancer Drug Discovery: Cell Cycle Control Targets" P01 CA078038
Dr. Said M. Sebti, Principal Investigator University of South Florida
Grant period: 9/1/1999 through 2/29/2004
"Combinatorial Creation of New Anticancer Agents" P01 CA083155
Dr. David H. Sherman, Principal Investigator University of Minnesota
Grant period: 9/23/1999 through 8/31/2005
Abstracts of the archive projects may be found in CRISP by entering the PI’s name, then Program Projects and Centers (P)under Activity and a year in which the grant was active http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen
Accomplishments:
Dr. Dennis Curran, under the Biology-Chemistry Center headed by Dr. John Lazo, discovered a major technological innovation he terms "fluorous mixture synthesis". This technique allows multiple natural product analogs to be produced in a single multi-step synthesis. He prepared four analogs of discodermolide by mixing precursors bearing four different groups at C22, each with a unique fluorous p-methoxybenzyl substituent as a tag on the C17 hydroxy group, and taking them through a nine-step sequence. Demixing by fluorous chromatography followed by deprotection and purification provided the individual analogs in 3- 7% overall yields and with a saving of 24 synthetic steps.
Dennis P. Curran and Takashi Furukawa, Organic Letters, 2002, 4, 2233.
Drs. Dale Boger and David Cheresh, under the Center headed by Dr. Peter K. Vogt, employed combinatorial chemistry to uncover a small molecule matrix metalloproteinase (MMP2) antagonist. This polyamide molecule disrupted the interaction of MMP2 and integrin, two proteins involved in angiogenesis and showed suppression of the growth of transplanted melanoma tumors. Evidence was provided that the compound's effect was not directly on the tumor itself but rather on the vasculature and there was the hope for reduced treatment-related toxicity.
Dale L. Boger, Joel Goldberg, Steve Silletti, Torsten Kessler and David A. Cheresh, J. Am. Chem. Soc 2001, 123, 1280-1288.
Steve Silletti, Torsten Kessler, Joel Goldberg, Dale L. Boger and David A. Cheresh, Proc. Natl. Acad. Sci. U.S.A., 2001, 98, 119-124.
The Biology-Chemistry Center headed by Dr. Said M. Sebti discovered a novel agent, GFB-111, that binds to a platelet-derived growth factor and has antiangiogenic and anticancer activity against human tumors in nude mice. For more information, see Blaskovich MA, Lin Q, Delarue FL, Sun J, Park HS, Coppola D, Hamilton AD, Sebti SM. Design of GFB-111, a platelet-derived growth factor binding molecule with antiangiogenic and anticancer activity against human tumors in mice. Nat Biotechnol 2000 Oct;18(10):1065-79