AG2034: a novel inhibitor of glycinamide ribonucleotide formyltransferase.

The glycinamide ribonucleotide formyltransferase (GARFT) inhibitor, 4-[2-(2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-6] [1,4]thiazin-6-yl)-(S)-ethyl]-2,5-thienoyl-L-glutamic acid (AG2034), was designed from the X-ray structure of the GARFT domain of the human tri functional enzyme. AG2034 inhibits human GARFT (Ki = 28 nM), has a high affinity for the folate receptor (Kd = 0.0042 nM), and is a substrate for rat liver folylpolyglutamate synthetase (K(m) = 6.4 microM, Vmax = 0.48 nmole/hr/mg). The IC50 for growth inhibition was 4 nM against L1210 cells and 2.9 nM for CCRF-CEM cells in culture. In vitro growth inhibition can be reversed by addition of either hypoxanthine or AICA (5-aminoimidazole-4-carboxamide) to the culture medium. A cell line with impaired transport of reduced folates, L1210/C1920, was resistant to AG2034 indicating that this compound can enter cells by utilizing the reduced folate carrier. AG2034 showed in vivo antitumor activity against the 6C3HED, C3HBA, and B-16 murine tumors and in the HxGC3, KM20L2, LX-1, and H460 human xenograft models, and has been selected for preclinical development towards clinical trials.

Matrix management: not a structure, a frame of mind.

In many of the world's leading corporations, strategic thinking has outdistanced organizational capability. As business challenges have grown more complex over the past 20 years, most companies have avoided the trap of one-dimensional strategic responses-stick to your knitting, stick to the big markets. But many of them have fallen into a second, structural trap and adopted elaborate organizational matrices that actually impair their ability to implement sophisticated strategies. Keeping a company light on its feet strategically while still coordinating its activities across divisions, functions, even continents, means eliminating parochialism, improving communications, and weaving the decision-making process into the company's social fabric. Altering formal structure from the top down is a poor way to achieve these goals. It is easier to work from the bottom up, focusing on the attitudes and behavior of individual managers. The companies that have made best use of this focus-among them NEC, Philips, and Unilever-employ three techniques to capture the capabilities and commitment of each manager: 1. They communicate a clear, consistent corporate vision. 2. They use training and career-path management to broaden individual perspectives and increase identification with corporate goals. 3. They co-opt individual energies and ambitions into the broader corporate-wide agenda. The goal is to build a matrix of corporate values and priorities in the minds of managers and let them make the judgments and negotiate the deals that make strategy pay off.