The best of 40 000: Detailed structure–activity‐relationship studies revealed key structural elements of indolin‐2‐on‐3‐spirothiazolidinones (see example) and their appropriate configuration for strong inhibitory activity against the pathophysiologically relevant title protein.

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The Ras/mitogen-activated protein (MAP) kinase signal transduction pathway regulates numerous biological programs including cell growth and differentiation, [1,2] and harbors several important anticancer-drug targets.[3] Recent research, in particular inspired by systems biology approaches, revealed the importance of dynamic spatiotemporal regulation of and interplay between the Ras network members and their interaction with other signaling modules for fully functional Ras signaling.[4] Because of their rapid, conditional, and reversible mode of action, small-molecule modulators of protein function are particularly suitable tools for the conditional analysis of such dynamic biological processes, and hold great promise for the study of biological systems.[5] Therefore, the identification of novel small-molecule modulators of signaling through the Ras network and the identification of their molecular targets are of major interest. [1,3,6] The naturally occurring tetramic acids melophlin A and B (1 and 2, Scheme 1 A) reverse the morphology of HRas-transformed NIH3T3 fibroblasts at a concentration of 5 mg mL À1 (that is, IC 50 = 14 mm). [7] However, the biological targets of the melophlins and their link to the Ras network have not been identified. Herein, we report the synthesis of a melophlin-inspired compound collection [8] and a subsequent chemical proteomics investigation, which revealed that melo- . Cells do not show cell-to-cell contacts, therefore E-cadherin is not enriched at the cell interfaces. f) E-cadherin immunostaining of MDCK-F3 cells. The arrow points to restored E-cadherin expression at the cell/cell interfaces after treatment with 20 mm U0126. g) E-cadherin staining of MDCK-F3 cells treated with 50 mm melophlin A (1). The arrow points to an example for restoration of E-cadherin expression at cell/cell interfaces. h) E-cadherin immunostaining of wild-type MDCK cells. E-cadherin immunostaining at the interfaces shows strong cellto-cell contact formation.

The Ras/mitogen-activated protein (MAP) kinase signal transduction pathway regulates numerous biological programs including cell growth and differentiation, [1,2] and harbors several important anticancer-drug targets.[3] Recent research, in particular inspired by systems biology approaches, revealed the importance of dynamic spatiotemporal regulation of and interplay between the Ras network members and their interaction with other signaling modules for fully functional Ras signaling.[4] Because of their rapid, conditional, and reversible mode of action, small-molecule modulators of protein function are particularly suitable tools for the conditional analysis of such dynamic biological processes, and hold great promise for the study of biological systems.[5] Therefore, the identification of novel small-molecule modulators of signaling through the Ras network and the identification of their molecular targets are of major interest. [1,3,6] The naturally occurring tetramic acids melophlin A and B (1 and 2, Scheme 1 A) reverse the morphology of HRas-transformed NIH3T3 fibroblasts at a concentration of 5 mg mL À1 (that is, IC 50 = 14 mm). [7] However, the biological targets of the melophlins and their link to the Ras network have not been identified. Herein, we report the synthesis of a melophlin-inspired compound collection [8] and a subsequent chemical proteomics investigation, which revealed that melo- . Cells do not show cell-to-cell contacts, therefore E-cadherin is not enriched at the cell interfaces. f) E-cadherin immunostaining of MDCK-F3 cells. The arrow points to restored E-cadherin expression at the cell/cell interfaces after treatment with 20 mm U0126. g) E-cadherin staining of MDCK-F3 cells treated with 50 mm melophlin A (1). The arrow points to an example for restoration of E-cadherin expression at cell/cell interfaces. h) E-cadherin immunostaining of wild-type MDCK cells. E-cadherin immunostaining at the interfaces shows strong cellto-cell contact formation.

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