Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors.

The discovery and optimization of a series of 6,7-dihydro-5H-cyclopenta[d]pyrimidine compounds that are ATP-competitive, selective inhibitors of protein kinase B/Akt is reported. The initial design and optimization was guided by the use of X-ray structures of inhibitors in complex with Akt1 and the closely related protein kinase A. The resulting compounds demonstrate potent inhibition of all three Akt isoforms in biochemical assays and poor inhibition of other members of the cAMP-dependent protein kinase/protein kinase G/protein kinase C extended family and block the phosphorylation of multiple downstream targets of Akt in human cancer cell lines.

Chk1 inhibition and Wee1 inhibition combine synergistically to impede cellular proliferation.

Inhibition of the checkpoint kinase Chk1, both as a monotherapy and in combination with DNA damaging cytotoxics, is a promising therapeutic approach for the treatment of a wide array of human cancers. However, much remains to be elucidated in regard to the patient populations that will respond best to a Chk1 inhibitor and the optimal therapeutics to combine with a Chk1 inhibitor. In an effort to discover sensitizing mutations and novel combination strategies for Chk1 inhibition, an siRNA screen was performed in combination with the selective Chk1 inhibitor AR458323.

Pyrazolopyridine Inhibitors of B-Raf(V600E). Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors.

The V600E mutation of B-Raf kinase results in constitutive activation of the MAPK signaling pathway and is present in approximately 7% of all cancers. Using structure-based design, a novel series of pyrazolopyridine inhibitors of B-Raf(V600E) was developed. Optimization led to the identification of 3-methoxy pyrazolopyridines 17 and 19, potent, selective, and orally bioavailable agents that inhibited tumor growth in a mouse xenograft model driven by B-Raf(V600E) with no effect on body weight.

Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors.

Herein we report the discovery and synthesis of a novel series of dihydrothieno- and dihydrofuropyrimidines (2 and 3) as potent pan Akt inhibitors. Utilizing previous SAR and analysis of the amino acid sequences in the binding site we have designed inhibitors displaying increased PKA and general kinase selectivity with improved tolerability compared to the progenitor pyrrolopyrimidine (1). A representative dihydrothieno compound (34) was advanced into a PC3-NCI prostate mouse tumor model in which it demonstrated a dose-dependent reduction in tumor growth and stasis when dosed orally daily at 200 mg/kg.

Discovery of pyrrolopyrimidine inhibitors of Akt.

The discovery and optimization of a series of pyrrolopyrimidine based protein kinase B (Pkb/Akt) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent inhibition of all three Akt isoforms and knockdown of phospho-PRAS40 levels in LNCaP cells and tumor xenografts.

Mcl-1 stability determines mitotic cell fate of human multiple myeloma tumor cells treated with the kinesin spindle protein inhibitor ARRY-520.

Kinesin spindle protein (KSP/Eg5) inhibitors are novel anticancer agents that have thus far shown only modest activity in the clinic. Understanding how to identify patients who may be most sensitive to treatment is clearly needed to improve the development of these molecules. We studied four multiple myeloma cell lines treated with the KSP inhibitor ARRY-520 to identify factors important for initiating apoptosis while cells are arrested in mitosis.