Son of sevenless homologue 1 (SOS1) is a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on RAS. In its active form, GTP-bound RAS is responsible for numerous critical cellular processes. Aberrant RAS activity is involved in ∼30% of all human cancers; hence, SOS1 is an attractive therapeutic target for its role in modulating RAS activation. Here, we describe a new series of benzimidazole-derived SOS1 agonists. Using structure-guided design, we discovered small molecules that increase nucleotide exchange on RAS in vitro at submicromolar concentrations, bind to SOS1 with low double-digit nanomolar affinity, rapidly enhance cellular RAS-GTP levels, and invoke biphasic signaling changes in phosphorylation of ERK 1/2. These compounds represent the most potent series of SOS1 agonists reported to date.

a dialkylzinc, the Pd(II) and Ni(II) catalysis leads to an alkylzinc iodide as shown by gravimetric analysis9 (eq 1).EtgZn (1.5 equiv.), neat Et,Zn (2 equiv.

No abstract

PTK2/FAK is a widely expressed non-receptor tyrosine kinase located mainly at focal adhesions. Sensing upstream signals from growth factor receptors as well as integrins, the enzyme contributes to activation of multiple downstream signaling pathways involved in the regulation of cell survival, proliferation and motility. PTK2 protein expression is elevated in many human cancers, and dysregulated PTK2 is known to mediate anchorage-independent growth of malignant cells. Inhibition of PTK2 activity thus may interfere with tumor growth and metastasis formation. BI 853520 inhibited the enzymatic activity of PTK2 at low nanomolar concentrations. In a selectivity screen of 264 tyrosine and serine/threonine kinases, BI 853520 inhibited only 4 enzymes at a concentration of 1,000 nM by more than 50%. In contrast to PTK2 inhibitors described previously, the compound showed more than 1,000-fold selectivity against closely related kinases such as PYK2/PTK2B. In human PC-3 prostate carcinoma cells, PTK2 is highly expressed and phosphorylated on Tyr397. Treatment of PC-3 cells with BI 853520 inhibited autophosphorylation with an EC50 of 1 nM. Colony formation of PC-3 cells in a soft agar matrix was inhibited with an EC50 of 3 nM. In contrast, the same cell line growing in conventional monolayer culture showed growth inhibition only at 1,000-fold higher concentration. Similar results were obtained for other carcinoma cell lines. BI 853520 administered to immunodeficient nude mice showed good oral bioavailability (F = 90%) and a half-life of 5 hours. Daily oral treatment at dose levels up to 100 mg/kg over a period of several weeks was well tolerated by the animals. Treatment with BI 853520 resulted in suppression of PTK2 autophosphorylation in tissue samples from both human tumor xenografts and mouse skin. BI 853520 was tested for efficacy in a panel of 18 human tumor xenograft models representing multiple indications, including carcinomas of the lung, ovary, pancreas and prostate as well as sarcomas. At daily oral doses of 50 mg/kg the compound was highly active in a subset of models, including the PC-3 prostate carcinoma, resulting in strong suppression of tumor growth (TGI > 90% compared to controls) or tumor regression in individual animals. Significant inhibition of tumor growth was observed at doses as low as 6 mg/kg, indicating a substantial therapeutic window and opportunities for combination therapy. Another subset of models showed intermediate drug sensitivity (TGI 40 − 80%), whereas several models were resistant to treatment (non-significant TGI). This database is currently being explored to identify biomarkers predicting sensitivity to BI 853520 based on genetic aberrations, gene expression signatures and phosphoproteome analysis of xenograft tumors. In conclusion, BI 853520 is a novel, highly selective PTK2 kinase inhibitor that demonstrates anti-tumor activity in vitro and in vivo. Clinical development of BI 853520 has recently been initiated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A249.

The reaction of functionalized dialkylzincs with photochemically generated Cr(CO)5-THF affords, after carbonylation and methylation using Meerwein's reagent, polyfunctional chromium carbene complexes in 35%-45% overall yield. The hydroboration of the unsaturated chromium carbene complex 4e followed by a boron-zinc exchange mediated by diethylzinc provides the dialkylzinc 6 bearing a chromium carbene functionality. This was reacted with deuterium oxide and iodine, affording the expected chromium carbene complexes in 67% and 43% yields, respectively.