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The diverse roles of deubiquitinatingenzymes, or DUBs, in determiningthe fate of specific proteins continue to unfold. Concurrent withthe revelation of DUBs as potential therapeutic targets are publicationsof small molecule inhibitors of these enzymes. In this review, wesummarize these molecules and their associated data and suggest additionalexperiments to further validate and characterize these compounds.We believe the field of drug discovery against DUBs is still in itsinfancy, but advances in assay development, biophysical techniques,and screening libraries hold promise for identifying suitable agentsthat could advance into the clinic. [ABSTRACT FROM AUTHOR]

Mitogen-activated protein kinasekinase kinase kinase 4 (MAP4K4)is a serine/threonine kinase implicated in the regulation of manybiological processes. A fragment-based lead discovery approach wasused to generate potent and selective MAP4K4 inhibitors. The fragmenthit pursued in this article had excellent ligand efficiency (LE),an important attribute for subsequent successful optimization intodrug-like lead compounds. The optimization efforts eventually ledus to focus on the pyridopyrimidine series, from which 6-(2-fluoropyridin-4-yl)pyrido[3,2-d]pyrimidin-4-amine (29) was identified. Thiscompound had low nanomolar potency, excellent kinase selectivity,and good in vivo exposure, and demonstrated in vivo pharmacodynamiceffects in a human tumor xenograft model. [ABSTRACT FROM AUTHOR]

Dysfunctional signalingthrough the phosphoinositide 3-kinase (PI3K)/AKT/mTORpathway leads to uncontrolled tumor proliferation. In the course ofthe discovery of novel benzoxepin PI3K inhibitors, we observed a strongdependency of in vivo antitumor activity on the free-drug exposure.By lowering the intrinsic clearance, we derived a set of imidazobenzoxazepincompounds that showed improved unbound drug exposure and effectivelysuppressed growth of tumors in a mouse xenograft model at low drugdose levels. One of these compounds, GDC-0032 (11l),was progressed to clinical trials and is currently under phase I evaluationas a potential treatment for human malignancies. [ABSTRACT FROM AUTHOR]

Several immunotherapy approaches that mobilize CD8 + T cell responses stimulate tumor rejection, and some, such as checkpoint blockade, have been approved for several cancer indications and show impressive increases in patient survival. However, tumors may evade CD8 + T cell recognition via loss of MHC molecules or because they contain few or no neoantigens. Therefore, approaches are needed to combat CD8 + T cell-resistant cancers. STING-activating cyclic dinucleotides (CDNs) are a new class of immune-stimulating agents that elicit impressive CD8 + T cell-mediated tumor rejection in preclinical tumor models and are now being tested in clinical trials. Here, we demonstrate powerful CDN-induced, natural killer (NK) cell-mediated tumor rejection in numerous tumor models, independent of CD8 + T cells. CDNs enhanced NK cell activation, cytotoxicity, and antitumor effects in part by inducing type I interferon (IFN). IFN acted in part directly on NK cells in vivo and in part indirectly via the induction of IL-15 and IL-15 receptors, which were important for CDN-induced NK activation and tumor control. After in vivo administration of CDNs, dendritic cells (DCs) up-regulated IL-15Rα in an IFN-dependent manner. Mice lacking the type I IFN receptor specifically on DCs had reduced NK cell activation and tumor control. Therapeutics that activate NK cells, such as CDNs, checkpoint inhibitors, NK cell engagers, and cytokines, may represent next-generation approaches to cancer immunotherapy., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Signaling pathways intersecting with the p21-activated kinases (PAKs) play important roles in tumorigenesis and cancer progression. By recognizing that the limitations of FRAX1036 (1) were chiefly associated with the highly basic amine it contained, we devised a mitigation strategy to address several issues such as hERG activity. The 5-amino-1,3-dioxanyl moiety was identified as an effective means of reducing pK a and logP simultaneously. When positioned properly within the scaffold, this group conferred several benefits including potency, pharmacokinetics, and selectivity. Mouse xenograft PK/PD studies were carried out using an advanced compound, G-5555 (12), derived from this approach. These studies concluded that dose-dependent pathway modulation was achievable and paves the way for further in vivo investigations of PAK1 function in cancer and other diseases.

[reaction: see text] Ni-catalyzed reductive coupling of aryl alkynes (1) and enantiomerically enriched alpha-oxyaldehydes (2) afford differentiated anti-1,2-diols (3) with high diastereoselectivity and regioselectivity, despite the fact that the methoxymethyl (MOM) and para-methoxybenzyl (PMB) protective groups typically favor syn-1,2-diol formation in carbonyl addition reactions of this family of aldehydes.