Discovery of a novel class of highly potent, selective, ATP-competitive, and orally bioavailable inhibitors of the mammalian target of rapamycin (mTOR).

A series of novel, highly potent, selective, and ATP-competitive mammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepine scaffold have been identified. Lead optimization resulted in the discovery of inhibitors with low nanomolar activity and greater than 1000-fold selectivity over the closely related PI3K kinases. Compound 28 (XL388) inhibited cellular phosphorylation of mTOR complex 1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates. Furthermore, this compound displayed good pharmacokinetics and oral exposure in multiple species with moderate bioavailability. Oral administration of compound 28 to athymic nude mice implanted with human tumor xenografts afforded significant and dose-dependent antitumor activity.

Discovery of XL888: a novel tropane-derived small molecule inhibitor of HSP90.

With structural guidance, tropane-derived HTS hits were modified to optimize for HSP90 inhibition and a desirable in vivo profile. Through an iterative SAR development process 12i (XL888) was discovered and shown to reduce HSP90 client protein content in PD studies. Furthermore, efficacy experiments performed in a NCI-N87 mouse xenograft model demonstrated tumor regression in some dosing regimens.

Discovery of a novel series of potent and orally bioavailable phosphoinositide 3-kinase γ inhibitors.

The phosphoinositide 3-kinases (PI3Ks) have been linked to an extraordinarily diversified group of cellular functions making these enzymes compelling targets for the treatment of disease. A large body of evidence has linked PI3Kγ to the modulation of autoimmune and inflammatory processes making it an intriguing target for drug discovery. Our high-throughput screening (HTS) campaign revealed two hits that were nominated for further optimization studies. The in vitro activity of the first HTS hit, designated as the sulfonylpiperazine scaffold, was optimized utilizing structure-based design. However, nonoptimal pharmacokinetic properties precluded this series from further studies. An overlay of the X-ray structures of the sulfonylpiperazine scaffold and the second HTS hit within their complexes with PI3Kγ revealed a high degree of overlap. This feature was utilized to design a series of hybrid analogues including advanced leads such as 31 with desirable potency, selectivity, and oral bioavailability.

An experimental and computational investigation of the enantioselective deprotonation of Boc-piperidine.

The asymmetric deprotonation of N-Boc-piperidine (3) by the 1:1 complex of a sec-alkyllithium and (-)-sparteine has been investigated both experimentally and computationally. The lithiation of 3 with sec-BuL-(-)-sparteine at -78 degrees C, which is a much slower process than is the analogous deprotonation of N-Boc-pyrrolidine (1) and a minor reaction relative to the competing addition of sec-BuLi to the carbamate, proceeds with a moderate degree of selectivity (er = 87:13) for removal of the pro-S hydrogen of 3. The related deprotonation of N-Boc-4-tosyloxypiperidine (6) with two molar equiv of sec-BuL-(-)-sparteine also involves preferential transfer of the pro-S hydrogen. The computational study of the deprotonation of (3) by i-PrL-(-)-sparteine found that the proton that is preferentially transferred within three-component intermediate complex is the thermodynamically least acidic alpha-hydrogen of 3. The asymmetric deprotonation of 3 is calculated to proceed with poor enantioselectivity and to have an activation energy considerably higher than that calculated for deprotonation of N-Boc-pyrrolidine (1). The experimental and computational results are in good agreement.