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Born August 22, 1953, Dale L. Boger (seated) received his B.Sc. in chemistry from the University of Kansas (1975) and Ph.D. in chemistry from Harvard University (1980). Immediately following graduate school, he returned to the University of Kansas as a member of the faculty in the Department of Medicinal Chemistry (1979Chemistry ( −1985, moved to the Department of Chemistry at Purdue University (1985University ( −1991, and joined the faculty at The Scripps Research Institute (1991 to present) as the Richard and Alice Cramer Professor of Chemistry. His research interests span the fields of organic and bioorganic chemistry and include the development of synthetic methodology, the total synthesis of natural products, heterocyclic chemistry, bioorganic chemistry, medicinal chemistry, the study of DNA−agent and protein−ligand interactions, and antitumor agents.Christopher W. Boyce (standing left) was born January 30, 1972, and grew up in Richmond, MA. Following a year abroad at the Swiss Federal Institute (ETH-Zurich), he received his B.Sc. in chemistry from Rensselaer Polytechnic Institute (1994, summa cum laude). He is currently pursuing a Ph.D. under the direction of Professor Dale L. Boger where he is addressing the synthesis and evaluation of potent DNA alkylation agents related to the CC-1065 and duocarmycin families. Robert M. Garbaccio (standing right) was born on January 20, 1972, and grew up in Old Tappan, NJ. He received his B.A. in chemistry and graduated summa cum laude from Boston University in 1994 where he conducted research in the laboratory of Professor James S. Panek. Presently, he is pursuing a Ph.D. in chemistry at The Scripps Research Institute under the guidance of Professor Dale L. Boger where he is addressing the synthesis and evaluation of potent DNA alkylating agents from the duocarmycin and mitomycin families of antitumor antibiotics. Joel A. Goldberg (standing center) was born June 17, 1972, and grew up in Bedford, NH. After receiving his B.Sc. from Tufts University he joined Professor Boger's laboratory at The Scripps Research Institute where he is pursuing his Ph.D. in Chemistry. His research concentrates on the synthesis and evaluation of potent alkylating agents related to CC-1065 and the duocarmycins.

Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.

The examination of shortened, simplified, and extended analogs of duocarmycin SA is described and constitutes a detailed study of the role of linked DNA binding subunit. In addition to enhancing the DNA binding affinity and selectivity through minor groove noncovalent contacts, the studies in conjunction with those of the accompanying article illustrate that an extended rigid N2 amide substituent is required for catalysis of the DNA alkylation reaction. This activation for DNA alkylation is independent of pH, and we propose it results from a binding-induced conformational change in the agents which increases their inherent reactivity. The ground state destabilization of the substrate results from a twist in the linking amide that disrupts the vinylogous amide stabilization of the alkylation subunit and activates the agent for nucleophilic addition. This leads to preferential activation of the agents for DNA alkylation within the narrower, deeper AT-rich minor groove sites where the inherent twist in the linking amide and helical rise of the bound conformation is greatest. Thus, shape-selective recognition (preferential AT-rich noncovalent binding) and shape-dependent catalysis (induced twist in linking N2 amide) combine to restrict SN2 alkylation to accessible adenine N3 nucleophilic sites within the preferred binding sites. Additional ramifications of this DNA binding-induced conformational change on the reversibility of the DNA alkylation reaction are discussed. The results of the study illustrate the importance of the C5‘ methoxy group and the C6 methyl ester of duocarmycin SA, and a previously unrecognized role for these substituents is proposed.

Matrix metalloproteinase 2 (MMP2) can associate with integrin ␣v␤3 on the surface of endothelial cells, thereby promoting vascular invasion. Here, we describe an organic molecule (TSRI265) selected for its ability to bind to integrin ␣v␤3 and block ␣v␤3 interaction with MMP2. Although disrupting ␣v␤3͞MMP2 complex formation, TSRI265 has no effect on ␣v␤3 binding to its extracellular matrix ligand vitronectin and does not influence MMP2 activation or catalytic activity directly. However, TSRI265 acts as a potent antiangiogenic agent and thereby blocks tumor growth in vivo. These findings suggest that activated MMP2 does not facilitate vascular invasion during angiogenesis unless it forms a complex with ␣v␤3 on the endothelial cell surface. By disrupting endothelial cell invasion without broadly suppressing cell adhesion or MMP function, the use of compounds such as TSRI265 may provide a novel therapeutic approach for diseases associated with uncontrolled angiogenesis.