Pyrido[2,3-d]pyrimidin-7-one Inhibitors of Cyclin-Dependent Kinases

Abstract

The identification of 8-ethyl-2-phenylamino-8H-pyrido[2, 3-d]pyrimidin-7-one (1) as an inhibitor of Cdk4 led to the initiation of a program to evaluate related pyrido[2, 3-d]pyrimidin-7-ones for inhibition of cyclin-dependent kinases (Cdks). Analysis of more than 60 analogues has identified some clear SAR trends that may be exploited in the design of more potent Cdk inhibitors. The most potent Cdk4 inhibitors reported in this study inhibit Cdk4 with IC(50) = 0.004 microM ([ATP] = 25 microM). X-ray crystallographic analysis of representative compounds bound to the related kinase, Cdk2, reveals that they occupy the ATP binding site. Modest selectivity between Cdks is exhibited by some compounds, and Cdk4-selective inhibitors block pRb(+) cells in the G(1)-phase of the cell division cycle.

FRAX597, a Small Molecule Inhibitor of the p21-activated Kinases, Inhibits Tumorigenesis of Neurofibromatosis Type 2 (NF2)-associated Schwannomas

“…This cavity is typically hydrophobic and its accessibility depends on the size and position of the gatekeeper residue. For example, the BRAF and CDK2 kinases have small (Thr) and large (Phe) gatekeeper residues, respectively, allowing BRAF to have a larger cavity in this area creating what is known as a BRAF specificity pocket (46), while this region is essentially blocked off in CDK2 (47). In PAK1, the position of the Met-344 gatekeeper residue and the C-helix create a relatively large back cavity capable of accommodating the large 2-chloro-4-(thiazol-5-yl)phenyl moiety attached to the C6 position of the pyrido [2,3-d]pyrimidin-7-one ring system.…”

“…In PAK1, the position of the Met-344 gatekeeper residue and the C-helix create a relatively large back cavity capable of accommodating the large 2-chloro-4-(thiazol-5-yl)phenyl moiety attached to the C6 position of the pyrido [2,3-d]pyrimidin-7-one ring system. Interestingly, some pyrido [2,3-d]pyrimidin-7-one derivatives were previously described as potent cyclin-dependent kinases (CDKs) inhibitors (47,48). Some of them also contained a methyl-piperazine phenylamino substituent at the C2 position of the same pyrido [2,3-d]pyrimidin-7-one ring system as FRAX597 ( Fig.…”

In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00

“…A variety of chemical classes, which include purine analogues (21 -25), pyrimidine analogues (26)(27)(28), indenopyrazoles (29,30), pyridopyrimidines (31)(32)(33), pyrazolopyridines (34,35), indolocarbazoles (36), pyrrolocarbazoles (37,38), oxindoles (39,40), and aminothiozoles (41) have been developed as Cdk inhibitors. Several compounds that inhibit Cdk activity are currently in clinical trials, including flavopiridol, R-roscovitine (CYC-202), UCN-01 (7-hydroxystaurosporine), and BMS-387032 either as single agents or in combination.…”

p42/p44 MAPKs are intracellular targets of the CDK inhibitor purvalanol

“…So far, numerous specific CDK inhibitors have been identified on the basis of their ability to inhibit CDK1, CDK2 or CDK4: the purines olomoucine (Vesely et al, 1994), roscovitine de Azevedo et al, 1997); purvalanols (Gray et al, 1998;Chang et al, 1999;Villerbu et al, 2002), CVT-313 (Brooks et al, 1997), C2-alkylynated purines (Legraverend et al, 2000), H717 (Dreyer et al, 2001) and NU2058 (Arris et al, 2000), piperidine-substituted purines (Shum et al, 2001), toyocamycin (Park et al, 1996), flavopiridol (Losiewicz et al, 1994), indirubins (Hoessel et al, 1999;Leclerc et al, 2001), paullones Zaharevitz et al, 1999;Leost et al, 2000), g-butyrolactone (Kitagawa et al, 1993), hymenialdisine , indenopyrazoles (Nugiel et al, 2001), the pyrimidines NY6027 (Arris et al, 2000) and CGP60474 (Zimmermann, 1995), pyridopyrimidines (Barvian et al, 2000), the aminopyrimidine PNU 112455A (Clare et al, 2001), oxindoles (Kent et al, 1999;Davis et al, 2001), PD0183812 (Fry et al, 2001), cinnamaldehydes (Jeong et al, 2000), quinazolines (Shewchuk et al, 2000;Sielecki et al, 2001), fasclaplysin (Soni et al, 2000(Soni et al, , 2001, SU9516 (Lane et al, 2001) and benzocarbazoles (Carini et al, 2001). Despite their chemical diversity, these inhibitors all act by competing with ATP at the ATP-binding site of the kinase.…”