Katherine Lara

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.

Abstract A254: A phase 1 safety and pharmacokinetic (PK) study of PI3K/TORC1/TORC2 inhibitor, XL765 (SAR245409), in combination with erlotinib in patients (pts) with advanced solid tumors

Background: XL765 is an oral, selective inhibitor of Class I PI3Ks, as well as TORC1 and TORC2. The PI3K pathway is frequently dysregulated in cancer cells and has been implicated as a mediator of resistance to EGFR inhibitors. In preclinical studies, XL765 has demonstrated dose‐dependent target modulation in tumor xenograft models. In an ongoing Phase 1 single agent clinical study, XL765 has exhibited robust pharmacodynamic activity in diverse solid tumors. Methods: Pts with advanced solid tumors are enrolled in successive cohorts of 3 to receive escalating doses of XL765 in combination with erlotinib. Cycles consist of 28 days of XL765 and erlotinib, each given qd. During the ongoing dose‐escalation phase of the study there is a 14‐day run‐in period of erlotinib monotherapy. Cycle 1 safety data determine dose limiting toxicities (DLTs). Tumor response is evaluated every 8 weeks. Results: As of 24Aug2009, 14 pts with advanced solid tumors have been enrolled: NSCLC (11), CRC (1), liposarcoma (1), and endometrial adenocarcinoma (1). Most of the NSCLC pts have been previously treated with erlotinib before entering the study. Pts have been treated at 2 dose levels of XL765 (30 and 50 mg) administered once‐daily in combination with 100 mg erlotinib. No DLTs or study treatment‐related SAEs have been reported. As of 03Aug2009, AEs have been reported for 7 pts. Grade 3 adverse events of nausea, vomiting, and anorexia considered related to study treatment were observed in one pt dosed at 30 mg qd. The PK of XL765 given in combination with erlotinib is consistent with that observed for XL765 given alone (Exelixis study XL765‐001). Likewise, XL765 does not appear to alter the PK of erlotinib. In skin biopsies, substantial post‐dose reductions were evident in phosphorylation of AKT, the mTOR substrate 4EBP1, and EGFR. For example, progressive pharmacodynamic effects were evident in serial skin biopsies from a pt with EGFR‐mutant NSCLC previously treated with erlotinib who has remained on study through 26 weeks, culminating in decreases in pAKT‐T308 (72%), p4EBP1 (57%), pERK (73%), and pEGFR (50%) at Day 85 post‐start of combination dosing (50 mg XL765/100 mg erlotinib). Pharmacodynamic analyses of paired tumor biopsies are in progress. Of the first 9 patients enrolled, five have remained on study for at least 12 weeks. Conclusions: XL765 in combination with erlotinib is generally well tolerated at doses up to 50 mg XL765/100 mg erlotinib, with no apparent drug‐drug PK interaction, and results in robust simultaneous inhibition of PI3K and EGFR signaling. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A254.