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A new strategy to create highly redox-responsive H-bond dimers based on proton-coupled electron transfer is proposed that capitalizes on the importance of secondary H-bonds in determining overall binding strength in H-bond dimers. Electron transfer induced proton transfer across a H-bond can be used to significantly strengthen the overall binding by both creating strong ionic H-bonds and changing the secondary H-bonds from unfavorable to favorable. The viability and potency of this approach are demonstrated with an electroactive DAD (A = H-acceptor, D = H-donor) array, H(MQ+)H, paired with an electroinactive ADA array, O(NH)O. NMR titration of H(MQ+)H with O(NH)O in 0.1 M NBu4PF6/CD2Cl2 gives a Kassoc of 500 M-1, typical of DAD-ADA dimers. However, upon two-electron reduction in 0.1 M NBu4PF6/CH2Cl2, cyclic voltammetry studies indicate a 1.8 × 105 increase in binding strength, corresponding to a very large Kassoc of 9 × 107 M-1. The latter value is typical of DDD-AAA H-bond dimers, consistent with proton transfer across the central H-bond upon reduction.

Diarylamines and related scaffolds are among the most common chemotypes in modern drug discovery. While they can potentially possess two chiral axes, there are no studies on their enantioselective ...

Lemur tyrosine kinase 3 (LMTK3) is oncogenic in various cancers. In breast cancer, LMTK3 phosphorylates and modulates the activity of estrogen receptor-α (ERα) and is essential for the growth of ER-positive cells. LMTK3 is highly expressed in ER-negative breast cancer cells, where it promotes invasion via integrin β1. LMTK3 abundance and/or high nuclear expression have been linked to shorter disease free and overall survival time in a variety of cancers, supporting LMTK3 as a potential target for anticancer drug development. We sought to identify small molecule inhibitors of LMTK3 with the ultimate goal to pharmacologically validate this kinase as a novel target in cancer. We used a homogeneous time resolve fluorescence (HTRF) assay to screen a collection of mixture-based combinatorial chemical libraries containing over 18 million compounds. We identified several cyclic guanidine-linked sulfonamides with sub-micromolar activity and evaluated their binding mode using a 3D homology model of the LMTK3 KD.

Unstable atropisomerism is innate in many common scaffolds in drug discovery, commonly existing as freely rotating aryl-aryl bonds. Such compounds can access the majority of dihedral conformations around the bond axis; however, most small molecules bind their target within a narrow range of these available conformations. The remaining accessible conformations can interact with other proteins leading to compound promiscuity. Herein, we leverage atropisomerism to restrict the accessible low-energy dihedral conformations available to a promiscuous kinase inhibitor and achieve highly selective and potent inhibitors of the oncogenic target rearranged during transfection (RET) kinase. We then evaluate our lead inhibitor against kinases that were predicted to bind compounds in a similar conformational window to RET, discovering a potent inhibitor of drug-resistant epidermal growth factor receptor (EGFR) mutants including L858R/T790M/C797S EGFR. Leveraging atropisomerism to restrict accessible conformational space should be a generally applicable strategy due to the prevalence of unstable atropisomerism in drug discovery.

The catalytic enantioselective synthesis of 3-aryl-substituted pyrrolopyrimidines (PPYs), a common motif in drug discovery, is achieved through a kinetic resolution via quaternary ammonium salt-catalyzed nucleophilic aromatic substitution (S(N)Ar). Both enantioenriched products and starting materials can be functionalized with no observed racemization to give enantiodivergent access to diverse chiral analogues of an important class of kinase inhibitor. One of the compounds was found to be a potent and selective inhibitor of breast tumor kinase.