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Constitutive Btk signaling drives several B-cell cancers. Here the authors demonstrate key allosteric intramolecular interactions between the SH2 domain and the kinase domain of Btk, and propose an alternative approach for inhibition of both wild-type and tyrosine kinase inhibitor-resistant Btk.

Summary: CDC42 family GTPases (RHOJ, RHOQ, CDC42) are upregulated but rarely mutated in cancer and control both the ability of tumor cells to invade surrounding tissues and the ability of endothelial cells to vascularize tumors. Here, we use computer-aided drug design to discover a chemical entity (ARN22089) that has broad activity against a panel of cancer cell lines, inhibits S6 phosphorylation and MAPK activation, activates pro-inflammatory and apoptotic signaling, and blocks tumor growth and angiogenesis in 3D vascularized microtumor models (VMT) in vitro. Additionally, ARN22089 has a favorable pharmacokinetic profile and can inhibit the growth of BRAF mutant mouse melanomas and patient-derived xenografts in vivo. ARN22089 selectively blocks CDC42 effector interactions without affecting the binding between closely related GTPases and their downstream effectors. Taken together, we identify a class of therapeutic agents that influence tumor growth by modulating CDC42 signaling in both the tumor cell and its microenvironment.

Fyn is a member of the Src-familyof nonreceptor protein–tyrosinekinases. Its abnormal activity has been shown to be related to varioushuman cancers as well as to severe pathologies, such as Alzheimer’sand Parkinson’s diseases. Herein, a structure-based drug designprotocol was employed aimed at identifying novel Fyn inhibitors. Twohits from commercial sources (1, 2) werefound active against Fyn with Kiof about2 μM, while derivative 4a, derived from our internallibrary, showed a Kiof 0.9 μM.A hit-to-lead optimization effort was then initiated on derivative 4ato improve its potency. Slightly modifications rapidlydetermine an increase in the binding affinity, with the best inhibitors 4cand 4dhaving Kis of 70 and 95 nM, respectively. Both compounds were found able toinhibit the phosphorylation of the protein Tau in an Alzheimer’smodel cell line and showed antiproliferative activities against differentcancer cell lines. [ABSTRACT FROM AUTHOR]