A small molecule called PD 153035 inhibited the epidermal growth factor (EGF) receptor tyrosine kinase with a 5-pM inhibition constant. The inhibitor was specific for the EGF receptor tyrosine kinase and inhibited other purified tyrosine kinases only at micromolar or higher concentrations. PD 153035 rapidly suppressed autophosphorylation of the EGF receptor at low nanomolar concentrations in fibroblasts or in human epidermoid carcinoma cells and selectively blocked EGF-mediated cellular processes including mitogenesis, early gene expression, and oncogenic transformation. PD 153035 demonstrates an increase in potency over that of other tyrosine kinase inhibitors of four to five orders of magnitude for inhibition of isolated EGF receptor tyrosine kinase and three to four orders of magnitude for inhibition of cellular phosphorylation.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib are effective treatments for a subset of non-small cell lung cancers. In particular, cancers with specific EGFR-activating mutations seem to be the most sensitive to these agents. However, despite their initial response, such cancers almost invariably develop resistance. In 50% of such cancers, a secondary EGFR mutation, T790M, has been identified that renders gefitinib and erlotinib ineffective inhibitors of EGFR kinase activity. Thus, there is a clinical need to develop novel EGFR inhibitors that can effectively inactivate T790M-containing EGFR proteins. In this study, we evaluate the effectiveness of a novel compound, PF00299804, an irreversible pan-ERBB inhibitor. The results from these studies show that PF00299804 is a potent inhibitor of EGFR-activating mutations as well as the EGFR T790M resistance mutation both in vitro and in vivo. Additionally, PF00299804 is a highly effective inhibitor of both the wild-type ERBB2 and the gefitinib-resistant oncogenic ERBB2 mutation identified in lung cancers. These preclinical evaluations support further clinical development of PF00299804 for cancers with mutations and/or amplifications of ERBB family members. [Cancer Res 2007;67(24):11924-32]

A class of high-affinity inhibitors is disclosed that selectively target and irreversibly inactivate the epidermal growth factor receptor tyrosine kinase through specific, covalent modification of a cysteine residue present in the ATP binding pocket. A series of experiments employing MS, molecular modeling, site-directed mutagenesis, and 14 C-labeling studies in viable cells unequivocally demonstrate that these compounds selectively bind to the catalytic domain of the epidermal growth factor receptor with a 1:1 stoichiometry and alkylate Cys-773. While the compounds are essentially nonreactive in solution, they are subject to rapid nucleophilic attack by this particular amino acid when bound in the ATP pocket. The molecular orientation and positioning of the acrylamide group in these inhibitors in relation to Cys-773 entirely support these results as determined from docking experiments in a homology-built molecular model of the ATP site. Evidence is also presented to indicate that the compounds interact in an analogous fashion with erbB2 but have no activity against the other receptor tyrosine kinases or intracellular tyrosine kinases that were tested in this study. Finally, a direct comparison between 6-acrylamido-4-anilinoquinazoline and an equally potent but reversible analog shows that the irreversible inhibitor has far superior in vivo antitumor activity in a human epidermoid carcinoma xenograft model with no overt toxicity at therapeutically active doses. The activity profile for this compound is prototypical of a generation of tyrosine kinase inhibitors with great promise for therapeutic significance in the treatment of proliferative disease.Considerable evidence has emerged, both preclinically and clinically, over the last decade to implicate the epidermal growth factor (EGF) receptor (EGFr) and erbB2 in the development, progression, and severity of certain human cancers. More recently, however, it has become clear that these receptors can intensify the transforming signal in a synergistic manner through their ability to form both homo-and heterodimers (1-7). Coexpression of the EGFr and erbB2 to levels where either receptor alone had little effect was highly transforming (8 -10). The association between overexpression and͞or constitutive activation of members of the type 1 receptor TK family (11) as well as coexpression of their cognate ligands (EGF, the heregulin family, transforming growth factor-␣, betacellulin) and transformation has been well established in many primary tumors. In particular, high expression levels of the EGFr and erbB2 have been frequently observed in breast, prostate, ovarian, and various squamous cell carcinomas in which overexpression positively correlates with shortened survival times and increased relapse rates (12-21).Over the past decade drug discovery efforts have produced a wide variety of chemical structures, generated either by synthetic means or as fermentation products, that reportedly inhibit purified or partially purified preparations of the EGFr tyrosine ki...

A novel catalytic dehydrocoupling route for the synthesis of linear, cyclic, and polymeric phosphinoboranes has been developed. The dehydrocoupling of neat Ph 2 PH‚BH 3 , which is otherwise very slow below 170 °C, is catalyzed by [{Rh(µ-Cl)(1,5-cod)} 2 ] or [Rh(1,5-cod) 2 ][OTf] (0.5-1 mol % Rh) to give the linear compound Ph 2 PH-BH 2 -PPh 2 -BH 3 (1) at 90 °C, and a mixture of the cyclic trimer [Ph 2 P-BH 2 ] 3 (2a) and tetramer [Ph 2 P-BH 2 ] 4 (2b) at 120 °C. In addition, the catalytic potential of other (e.g., Ti, Ru, Rh, Ir, Pd, Pt) complexes toward the dehydrocoupling of Ph 2 PH‚BH 3 was investigated and was in many cases demonstrated. The molecular structures of 1 and 2b, and of the primary phosphine-borane adduct PhPH 2 ‚ BH 3 , were determined by single-crystal X-ray analysis. The dehydrogenative coupling of PhPH 2 ‚BH 3 gave low-molecular-weight poly(phenylphosphinoborane) [PhPH-BH 2 ] n (3) when performed in toluene (110 °C) with ca. 0.5 mol % [Rh(1,5-cod) 2 ][OTf] as catalyst. The absolute weight-average molecular weight was determined by static light scattering (SLS) in THF which showed that M w ) 5600. Samples of high-molecularweight polymer 3 (M w ) 31 000 or 33 300 by SLS) were synthesized using neat conditions at 90-130 °C in the presence of [{Rh(µ-Cl)(1,5-cod)} 2 ], anhydrous RhCl 3 , or RhCl 3 hydrate (ca. 1 mol % Rh). Poly-(phosphinoborane) 3 was thereby obtained in ca. 75% yield as an air-stable, off-white solid and was structurally characterized by 1 H, 11 B, 13 C, and 31 P NMR and IR spectroscopy and elemental analysis. The hydrodynamic diameters for polymers 3 in THF were also determined by dynamic light scattering (DLS). Catalytic dehydrocoupling of the alkyl-substituted phosphine-borane adduct iBuPH 2 ‚BH 3 was also investigated and was found to be much slower than that of PhPH 2 ‚BH 3 . This produced poly(isobutylphosphinoborane) [iBuPH-BH 2 ] n (4) under neat conditions at 120 °C in the presence of [{Rh(µ-Cl)(1,5-cod)} 2 ] in 80% yield. Multinuclear NMR spectroscopy and DLS were also used to characterize polymer 4, and the latter indicated that M w ) ca. 10 000-20 000. Prolonged heating of polymers 3 and 4 at elevated temperatures in the presence of catalyst led to insoluble but solvent-swellable gels possibly due to light interchain cross-linking through P-B bonds. In the absence of rhodium catalyst thermally induced dehydrocoupling of PhPH 2 ‚BH 3 and iBuPH 2 ‚BH 3 proceeds very slowly and forms only low-molecular-weight materials with complex NMR spectra and which probably possess a branched structure.