Gingipains from Porphyromonas gingivalis drive Alzheimer’s pathology and can be blocked with small-molecule inhibitors.

Mutations in the neurofibromatosis type 2 (NF2) gene that limit or abrogate expression of functional Merlin are common in malignant mesothelioma. Merlin activates the Hippo pathway to suppress nuclear translocation of YAP and TAZ, the major effectors of the pathway that associate with the TEAD transcription factors in the nucleus and promote expression of genes involved in cell proliferation and survival. In this article, we describe the discovery of compounds that selectively inhibit YAP/TAZ-TEAD promoted gene transcription, block TEAD auto-palmitoylation, and disrupt interaction between YAP/TAZ and TEAD. Optimization led to potent analogs with excellent oral bioavailability and pharmacokinetics that selectively inhibit NF2-deficient mesothelioma cell proliferation in vitro and growth of subcutaneous tumor xenografts in vivo. These highly potent and selective TEAD inhibitors provide a way to target the Hippo-YAP pathway, which thus far has been undruggable and is dysregulated frequently in malignant mesothelioma and in other YAP-driven cancers and diseases.

UDP‐3‐O‐(R‐3‐hydroxymyristoyl)‐N‐acetylglucosamine deacetylase (LpxC) is a Zn2+ deacetylase that is essential for the survival of most pathogenic Gram‐negative bacteria. ACHN‐975 (N‐((S)‐3‐amino‐1‐(hydroxyamino)‐3‐methyl‐1‐oxobutan‐2‐yl)‐4‐(((1R,2R)‐2‐(hydroxymethyl)cyclopropyl)buta‐1,3‐diyn‐1‐yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose‐limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. Herein we report the effort beyond ACHN‐975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on its overall profile, compound 26 (LPXC‐516, (S)‐N‐(2‐(hydroxyamino)‐1‐(3‐methoxy‐1,1‐dioxidothietan‐3‐yl)‐2‐oxoethyl)‐4‐(6‐hydroxyhexa‐1,3‐diyn‐1‐yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided a solubility of >30 mg mL−1 for parenteral administration and conversion into the active drug with a t1/2 of approximately two minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development.

Polo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of α-synuclein in Lewy bodies, which are one of the hallmarks of Parkinson's disease neuropathology. Potent, selective, brain-penetrant inhibitors of Plk-2 were obtained from a structure-guided drug discovery approach driven by the first reported Plk-2-inhibitor complexes. The best of these compounds showed excellent isoform and kinome-wide selectivity, with physicochemical properties sufficient to interrogate the role of Plk-2 inhibition in vivo. One such compound significantly decreased phosphorylation of α-synuclein in rat brain upon oral administration and represents a useful probe for future studies of this therapeutic avenue toward the potential treatment of Parkinson's disease.

The 1,2-diol unit is one of the most ubiquitous functional groups in nature, and consequently a wealth of methods leading to its synthesis have been developed. Foremost in this arsenal are the catalytic osmylation of olefins,1 ring opening of epoxides,2 and reduction or alkylation of -hydroxy/alkoxy carbonyls.3 Common(1) (a) Wai,