Cyclin-dependent kinases (CDK) are key positive regulators of cell cycle progression and attractive targets in oncology. SCH 727965 inhibits CDK2, CDK5, CDK1, and CDK9 activity in vitro with IC 50 values of 1, 1, 3, and 4 nmol/L, respectively. SCH 727965 was selected as a clinical candidate using a functional screen in vivo that integrated both efficacy and safety parameters. Compared with flavopiridol, SCH 727965 exhibits superior activity with an improved therapeutic index. In cell-based assays, SCH 727965 completely suppressed retinoblastoma phosphorylation, which correlated with apoptosis onset and total inhibition of bromodeoxyuridine incorporation in >100 tumor cell lines of diverse origin and background. Moreover, short exposures to SCH 727965 were sufficient for long-lasting cellular effects. SCH 727965 induced regression of established solid tumors in a range of mouse models following intermittent scheduling of doses below the maximally tolerated level. This was associated with modulation of pharmacodynamic biomarkers in skin punch biopsies and rapidly reversible, mechanism-based effects on hematologic parameters. These results suggest that SCH 727965 is a potent and selective CDK inhibitor and a novel cytotoxic agent. Mol Cancer Ther; 9(8); 2344-53. ©2010 AACR.

OVER a wide range of ages, the mortality from various types of human cancer rises approximately in proportion to a high power of the age, and Muller (1951), Nordling (1953) and Stocks (1953) have independently suggested that this could be accounted for if the development of cancer were the end-result of a series of discrete cellular changes-such, for example, as would be produced by somatic mutations.In a previous paper we tested the hypothesis by examining separately the relationship between age and mortality for cancer of several different sites in men and in women (Armitage and Doll, 1954). As a result, we concluded that several of the other principal epidemiological characteristics of human cancer could also be accounted for if carcinogenesis were a complex process of six or seven stages and the degree of exposure to the factors inducing the changes from one stage to another varied, either with age or from one year to another. In particular, the hypothesis could account for:(1) The differences between the shapes of the curves relating mnortality to age, observed for different sites;(2) the long latent period observed after exposure to a carcinogen before a tumour develops; (3) clinical observations such as the failure of circumcision carried out in adolescence to protect against cancer of the penis and (4) the apparent linearity of the relationship between cancer incidence and the concentration of the carcinogen to which the subject is exposed,.* The hypothesis was, however, unsatisfactory in that there was no direct experimental evidence to suggest that carcinogenesis was likely to involve more than two stages.If the incidence of cancer did, in fact, increase exactly in proportion to the 4th, 5th or 6th power of the age over the whole range of ages and the incidence of cancer at each age was directly proportional to the concentration of the initial carcinogen, it would be difficult to see how the facts could be explained by any * It is realized that the relationship is not linear in all circumstances-particularly when the incidence of cancer is high. There is, however, some evidence that the relationship can be linear at low doses and the existance of such a relationship has been accepted as a working hypothesis.

Crystallographic and thermodynamic studies of farnesyl protein transferase (FPT) complexed with novel tricyclic inhibitors provide insights into the observed SAR for this unique class of nonpeptidic FPT inhibitors. The crystallographic structures reveal a binding pattern conserved across the mono-, di-, and trihalogen series. In the complexes, the tricycle spans the FPT active site cavity and interacts with both protein atoms and the isoprenoid portion of bound farnesyl diphosphate. An amide carbonyl, common to the tricyclic compounds described here, participates in a water-mediated hydrogen bond to the protein backbone. Ten high-resolution crystal structures of inhibitors complexed with FPT are reported. Included are crystallographic data for FPT complexed with SCH 66336, a compound currently undergoing clinical trials as an anticancer agent (SCH 66336, 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5, 6]cyclohepta[1, 2-b]pyridin-11-yl)-1-piperidinyl]-2-oxoethyl]-1-piperidinecarbo xamide ). Thermodynamic binding parameters show favorable enthalpies of complex formation and small net entropic contributions as observed for 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-11H-benzo[5, 6]cyclohepta[1, 2-b]pyridin-11-ylidene)-1-piperidinyl]-2-oxoethyl]pyridine N-oxide where DeltaH degrees bind = -12.5 kcal/mol and TDeltaS degrees bind = -1.5 kcal/mol.

Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncology therapeutics. Herein is described the utilization of an in vivo screening approach with integrated efficacy and tolerability parameters to identify candidate CDK inhibitors with a suitable balance of activity and tolerability. This approach has resulted in the identification of SCH 727965, a potent and selective CDK inhibitor that is currently undergoing clinical evaluation.

Oncogenic forms of Ras proteins are associated with a broad range of human cancers including an estimated 90% of all colon cancers (1). Ras proteins undergo a complex series of posttranslational processing events, which have been defined over the past several years (2, 3). The initial post-translational event is the transfer of the 15-carbon isoprene farnesyl from farnesyl pyrophosphate to a Cys residue (Cys 186 in Ha-Ras) in the conserved carboxyl-terminal "CAAX" motif (where "A" is an aliphatic residue) present in all Ras proteins (4, 5). Studies employing site-directed mutagenesis (6, 7) or inhibitors of hydroxymethylglutaryl-CoA reductase (8), the rate-limiting enzyme in isoprenoid biosynthesis, demonstrated that isoprenylation is required for Ras proteins to become membraneassociated and to induce cellular transformation. The farnesyl protein transferase (FPT) 1 that catalyzes this reaction has been purified (9) and cDNA clones for its ␣ and ␤ subunits isolated (10 -12).A number of other cellular proteins are also isoprenylated on a Cys residue near their COOH terminus (13,14). These include other substrates for FPT, such as the nuclear lamins (15). However, the majority of cellular isoprenylated proteins are modified with geranylgeranyl, a 20-carbon isoprene. Two distinct geranylgeranyl protein transferases (GGPT I and II) have been identified (16,17) and cDNA clones for their ␣ and ␤ subunits isolated (18,19). GGPT I and FPT share a common ␣ subunit (18,20).The primary determinant for recognition of protein substrates by the isoprenyl transferases is the substrate's carboxyl-terminal amino acid sequence. Proteins ending in Cys-X-XSer (or Met) are preferred substrates for FPT, while proteins terminating in Cys-X-X-Leu are preferred substrates for GGPT I (21, 22). Substitution of leucine for serine at the COOH terminus of the Ha-Ras CAAX box (Ser 189 3 Leu) makes this protein a substrate for geranylgeranylation (rather than farnesylation) both in vitro and in cells (23). The different substrate specificities of FPT and GGPT-1 are likely mediated by their distinct ␤ subunits. GGPT II utilizes protein substrates terminating in Cys-Cys or Cys-X-Cys (17,24).A number of inhibitors of FPT have been reported over the past several years (25). The design of CAAX peptidomimetics (26 -29) has resulted in potent and selective FPT inhibitors capable of blocking Ras processing in cells. These compounds have shown considerable promise as antitumor agents based on their ability to inhibit cellular transformation induced by oncogenic Ras proteins (26,27) and the growth of Ras-dependent