Catch and Release DNA Decoys: Capture and Photochemical Dissociation of NF-κB Transcription Factors

Catch and release DNA decoys (CRDDs) are a new class of non-natural DNA probes that capture and dissociate from DNA-binding proteins using a light trigger. Photolytic cleavage of non-natural nucleobases in the CRDD yields abasic sites and truncation products that lower the affinity of the CRDD for its protein target. Herein, we demonstrate the ability of the first-generation CRDD to bind and release NF-κB proteins. This platform technology should be applicable to other DNA-binding proteins by modification of the target sequence

Bicyclic Cyclohexenones as Inhibitors of NF-κB Signaling

A series of structurally simplified cryptocaryone analogues were synthesized by a facile Pd-catalyzed acetoxylation of alkyne-tethered cyclohexadienones and evaluated as inhibitors of NF-κB signaling. Compounds <b>10</b> and <b>11</b> were found to possess low micromolar inhibitory properties toward induced NF-κB activity by blocking p50/p65 nuclear protein through a covalent inhibition mechanism. Both compounds were able to inhibit NF-κB-induced IL-8 expression and exhibited antiproliferative activity against two model cancer cell lines. These analogues constitute a promising new scaffold for the development of novel NF-κB inhibitors and anticancer agents

Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription

The transcription factor Max is a basic-helix-loop-helix leucine zipper (bHLHLZ) protein that forms homodimers or interacts with other bHLHLZ proteins, including Myc and Mxd proteins. Among this dynamic network of interactions, the Myc/Max heterodimer has crucial roles in regulating normal cellular processes, but its transcriptional activity is deregulated in a majority of human cancers. Despite this significance, the arsenal of high-quality chemical probes to interrogate these proteins remains limited. We used small molecule microarrays to identify compounds that bind Max in a mechanistically unbiased manner. We discovered the asymmetric polycyclic lactam, KI-MS2-008, which stabilizes the Max homodimer while reducing Myc protein and Myc-regulated transcript levels. KI-MS2-008 also decreases viable cancer cell growth in a Myc-dependent manner and suppresses tumor growth in vivo. This approach demonstrates the feasibility of modulating Max with small molecules and supports altering Max dimerization as an alternative approach to targeting Myc.National Cancer Institute (Grant R01-CA160860)National Cancer Institute (Grant P30-CA14051)National Cancer Institute (Grant U01-CA176152)National Cancer Institute (Grant CA170378PQ2)National Institutes of Health (Grant CA170378PQ2

Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors

© 2020 The Authors Castration-resistant prostate cancers (CRPCs) lose sensitivity to androgen-deprivation therapies but frequently remain dependent on oncogenic transcription driven by the androgen receptor (AR) and its splice variants. To discover modulators of AR-variant activity, we used a lysate-based small-molecule microarray assay and identified KI-ARv-03 as an AR-variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deduced KI-ARv-03 to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors. Further optimization resulted in KB-0742, an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo, oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC. In the pursuit of hormone receptor modulators in prostate cancer, a potent, ultraselective CDK9 inhibitor is discovered. This study describes the most selective inhibitors of CDK9 known to date and provides compelling preclinical in vitro and in vivo support for CDK9 as a therapeutic target