Deregulation of the ErbB (proto-oncogene B of the avian erythroblastosis virus AEV-H strain) receptor network is well recognized as an oncogenic driver in epithelial cancers. Several targeted drugs have been developed, including antibodies and small-molecule kinase inhibitors, each of them characterized by distinct patterns of ErbB receptor interactions. Understanding the precise pharmacological properties of these compounds is important for optimal use in clinical practice. Afatinib [BIBW 2992; N-[4-[(3-chloro-4-is an ATP-competitive anilinoquinazoline derivative harboring a reactive acrylamide group. It was designed to covalently bind and irreversibly block enzymatically active ErbB receptor family members. Here, we show by X-ray crystallography the covalent binding of afatinib to wild-type epidermal growth factor receptor (EGFR) and by mass spectrometry the covalent interaction with EGFR, EGFR L858R/T790M , human epidermal growth factor receptor 2 (HER2), and ErbB-4. Afatinib potently inhibits the enymatic activity of ErbB-4 (EC 50 ϭ 1 nM) and the proliferation of cancer cell lines driven by multiple ErbB receptor aberrations at concentrations below 100 nM., a close analog of afatinib lacking the acrylamide group and thus incapable of covalent bond formation, had similar potency on cells driven by EGFR or EGFR L858R , but less or no detectable activity on cells expressing EGFR L858R/ T790M HER2 or ErbB-4. These results stress the importance of the acrylamide group and show that afatinib differs from approved ErbB targeting agents by irreversibly inhibiting the kinase activity of all ErbB family members. They provide a mechanistic rationale for the distinct pharmacological features of this compound and explain the clinical activity seen in some patients who are resistant to antibody or kinase inhibitor therapy because of secondary mutations or ErbB receptor "reprogramming."

The effect of addition of the cyclodextrins (CDx) α-CDx and β-CDx on the photophysics and photochemistry of the dimethoxybenzenes (DMB) 1,4-DMB and 1,2-DMB in aqueous solution has been investigated by means of absorption, circular dichroism, fluorescence, and nanosecond transient absorption spectroscopies. The experimental results are discussed in the light of model calculations on the structure and the circular dichroism spectra of the DMB−CDx complexes. The association of 1,2-DMB with both CDxs is much weaker than that of 1,4-DMB owing to steric hindrance. With β-CDx, 1,4-DMB forms 1:1 complexes with a high association constant (K = 630 M-1) in spite of incomplete inclusion. Complexation of 1,4-DMB with α-CDx strongly affects the photophysical properties of the guest:  fluorescence is enhanced and triplet state decay slowed by a factor of 10 or more, depending on the decay reaction mode. Fluorescence enhancement is mainly due to a reduction of the rate constant for internal conversion. The effect of complexation on triplet decay was exploited for a detailed study of the association mechanism in terms of the consecutive formation of 1:1 and 1:2 complexes. Temperature-dependent measurements showed that both association steps are controlled by enthalpy−entropy compensation, the first step being entropy-driven and the second one enthalpy-driven. At lower temperatures (T < 50 °C), 1:2 complex formation predominates. These findings are supported by the circular dichroism spectra and the model calculations. There is no significant effect of complexation with either α- or β-CDx on hydrated electron ejection from 1,4-DMB, but the eaq - decay is accelerated in the presence of β-CDx. This is tentatively attributed to spatial correlation between eaq - and radical cations induced by complexation.

Rigorous runtime analyses of evolutionary algorithms (EAs) mainly investigate algorithms that use elitist selection methods. Two algorithms commonly studied are Randomized Local Search (RLS) and the (1+1) EA and it is well known that both optimize any linear pseudo-Boolean function on n bits within an expected number of O(n log n) fitness evaluations.In this paper, we analyze variants of these algorithms that use fitness proportional selection.A well-known method in analyzing the local changes in the solutions of RLS is a reduction to the gambler's ruin problem. We extend this method in order to analyze the global changes imposed by the (1+1) EA. By applying this new technique we show that with high probability using fitness proportional selection leads to an exponential optimization time for any linear pseudo-Boolean function with non-zero weights. Even worse, all solutions of the algorithms during an exponential number of fitness evaluations differ with high probability in linearly many bits from the optimal solution.Our theoretical studies are complemented by experimental investigations which confirm the asymptotic results on realistic input sizes.

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