Structure–Cytotoxicity Relationships of Analogues of <i>N</i>¹⁴-Desacetoxytubulysin H

Herein we report structure–cytotoxicity relationships for analogues of <i>N</i>¹⁴-desacetoxytubulyisn H <b>1</b>. A novel synthetic approach toward <b>1</b> enabled the discovery of compounds with a range of activity. Calculated basicity of the <i>N</i>-terminus of tubulysins was shown to be a good predictor of cytotoxicity. The impact of structural modifications at the C-terminus of <b>1</b> upon cytotoxicity is also described. These findings will facilitate the development of new tubulysin analogues for the treatment of cancer

Structure- and Reactivity-Based Development of Covalent Inhibitors of the Activating and Gatekeeper Mutant Forms of the Epidermal Growth Factor Receptor (EGFR)

A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH)-based assay was used to measure thiol reactivity toward the electrophilic functionality of the inhibitor series, enabling both the identification of a suitable reactivity window for their potency and the development of a reactivity quantitative structure-property relationship (QSPR) to support design