The design, synthesis, and biological evaluation of PIM kinase inhibitors.

A series of substituted benzofuropyrimidinones with pan-PIM activities and excellent selectivity against a panel of diverse kinases is described. Initial exploration identified aryl benzofuropyrimidinones that were potent, but had cell permeability limitation. Using X-ray crystal structures of the bound PIM-1 complexes with 3, 5m, and 6d, we were able to guide the SAR and identify the alkyl benzofuropyrimidinone (6l) with good PIM potencies, permeability, and oral exposure.

The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors.

Variously substituted indolin-2-ones were synthesized and evaluated for activity against KDR, Flt-1, FGFR-1 and PDGFR. Extension at the 5-position of the oxindole ring with ethyl piperidine (compound 7i) proved to be the most beneficial for attaining both biochemical and cellular potencies. Further optimization of 7i to balance biochemical and cellular potencies with favorable ADME/ PK properties led to the identification of 8h, a compound with a clean CYP profile, acceptable pharmacokinetic and toxicity profiles, and robust efficacy in multiple xenograft tumor models.

Design and evaluation of a series of pyrazolopyrimidines as p70S6K inhibitors.

The 70-kDa ribosomal protein S6 kinase (p70S6K) is part of the PI3K/AKT/mTOR pathway and has been implicated in cancer. High throughput screening versus p70S6K led to the identification of aminopyrimidine 3a as active inhibitor. Lead optimization of 3a resulted in highly potent, selective, and orally bioavailable pyrazolopyrimidines. In this manuscript we report the structure-activity relationship of this series and pharmacokinetic, pharmacodynamic, and efficacy data of the lead compound 13c.

Discovery of XL413, a potent and selective CDC7 inhibitor.

CDC7 is a serine/threonine kinase that has been shown to be required for the initiation and maintenance of DNA replication. Up-regulation of CDC7 is detected in multiple tumor cell lines, with inhibition of CDC7 resulting in cell cycle arrest. In this paper, we disclose the discovery of a potent and selective CDC7 inhibitor, XL413 (14), which was advanced into Phase 1 clinical trials. Starting from advanced lead 3, described in a preceding communication, we optimized the CDC7 potency and selectivity to demonstrate in vitro CDC7 dependent cell cycle arrest and in vivo tumor growth inhibition in a Colo-205 xenograft model.

Pyrazolopyrimidines as dual Akt/p70S6K inhibitors.

Activation of the PI3K/Akt/mTOR kinase pathway is frequently associated with human cancer. Selective inhibition of p70S6Kinase, which is the last kinase in the PI3K pathway, is not sufficient for strong tumor growth inhibition and can lead to activation of upstream proteins including Akt through relief of a negative feedback loop. Targeting multiple sites in the PI3K pathway might be beneficial for optimal activity. In this manuscript we report the design of dual Akt/p70S6K inhibitors and the evaluation of the lead compound 11b in vivo, which was eventually advanced into clinical development.

Day-3 embryo morphology predicts euploidy among older subjects.

OBJECTIVE: To evaluate whether day-3 embryo morphology predicts euploidy. DESIGN: Retrospective. SETTING: Private IVF center. PATIENT(S): Subjects (n = 144) undergoing in vitro fertilization and preimplantation genetic diagnosis (PGD). INTERVENTION(S): Translate day-3 embryo characteristics into a standardized score. MAIN OUTCOME MEASURE(S): Day-3 embryo morphology score and PGD fluorescence in situ hybridization results for chromosomes: 13, 15, 16, 17, 18, 21, 22, X, and Y. RESULT(S): Of 1,043 biopsied blastomeres, 67% (n = 696) were chromosomally abnormal. Women with advanced maternal age (AMA) were 1.3 times more likely to have chromosomal errors (95% CI 1.1-1.4) than younger subjects (<38 years old). Morphology predicted PGD results in the AMA group (n = 553), but not in younger women. Fragmentation predicted euploidy in both the younger and the AMA group, but cell number did not. CONCLUSION(S): Day-3 embryo morphology selects for euploidy among AMA subjects but not among younger women who may have other factors responsible for embryo dysmorphism. However, cellular fragmentation is a sensitive proxy for selecting chromosomally normal embryos in both age groups. It is unclear that PGD-aneuploidy screening is a better tool for selecting which embryos to transfer than the standard approach of using day-3 embryo features, particularly among older women, a group for whom this technology is targeted.