The BET bromodomain proteins BRD3 and BRD4 induce N-Myc expression, but do not function synergistically.

JQ1 and panobinostat do not cooperatively induce apoptosis in normal non-malignant cells.

Legends for Supplemental Figures S1-S8.

Supplemental Figure S1. Effect of HDAC and Hsp90 inhibitors on Hsp90 (α/β)/p23 interactions.

Supplemental Figure S7. Inhibition of UKE-1 cell proliferation by the lead HDAC inhibitor 1A12 alone and in combination with the Doxorubicin and Hsp90 inhibitor PU-H71.

Supplemental Methods. Description of additional methods and procedures used in the study.

Supplemental Figure S2. 17-DMAG enhanced the effect of Tubacin on inhibition of Hsp90(α/β)/p23 interactions.

The BET bromodomain protein BRD2 does not regulate N-Myc expression.

Supplemental Figure S8. Analyses of HDAC biomarkers in tumor xenografts in mice treated with 1A12.

Supplemental Table S1. Selectivity of lead HDAC inhibitors for inhibition of HDAC1-9 activities in vitro.

The top 35 genes most dramatically down-regulated by JQ1 and panobinostat combination therapy.

Supplemental Figure S6. Specificity of 1A12 in inhibition of HDAC6.

Combination therapy with JQ1 and panobinostat exerts synergistic anticancer effects in neuroblastoma cells.

Supplemental Figure S4. Up-regulation of HDAC biomarkers (p21waf1 and acetylated H3), Hsp70 and NRL-p23 fusion reporter in cells treated with lead HDAC inhibitors.

JQ1 and panobinostat do not cooperatively regulate GSK3β and Aurora A expression, and LIN28B does not regulate Aurora A expression.

JQ1 and panobinostat synergistically modulate gene expression.

Supplemental Figure S5. Determination of the specificity of 1A12 in inhibition of HDACs.

Supplemental Figure S3. Syntheses and characterization of lead HDAC inhibitors.

Abstract Growing malignant tumors must evade destruction by the immune system, a hurdle some malignancies overcome by attracting immune-suppressive regulatory T-cells (Tregs)1. The IKZF2 (Helios) transcription factor plays a crucial role in maintaining function and stability of Tregs, and IKZF2 deficiency enhances immune responses to tumors in mice2, suggesting IKZF2 may be an attractive target for cancer immunotherapy. Here we describe the discovery and characterization of DKY709, the first molecular glue degrader of IKZF2/4 which spares IKZF1/3. DKY709 was identified through a recruitment-guided medicinal chemistry campaign that redirected the degradation selectivity of CRBN binders towards IKZF2. The IKZF transcription factor selectivity of DKY709 was rationalized by the X-ray structure of the CRBN-DKY709-IKZF2(ZF2) ternary complex. Upon exposure to DKY709, human Tregs showed reduced suppressive activity and exhausted T-effector cells recovered IFNγ production. In vivo, oral treatment with DKY709 drove a rapid and sustained degradation of IKZF2 including in humans and led to delayed tumor growth in mice with humanized immune systems and enhanced immunization responses in monkeys. DKY709 is a first-in-class, potent and selective oral IKZF2/4 degrader currently being investigated in a phase 1 clinical trial as an immune-enhancing agent for cancer immunotherapy.

The NIH Virtual SARS-CoV-2 Antiviral Summit, held on 6 November 2020, was organized to provide an overview on the status and challenges in developing antiviral therapeutics for coronavirus disease 2019 (COVID-19), including combinations of antivirals. Scientific experts from the public and private sectors convened virtually during a live videocast to discuss severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets for drug discovery as well as the preclinical tools needed to develop and evaluate effective small-molecule antivirals. The goals of the Summit were to review the current state of the science, identify unmet research needs, share insights and lessons learned from treating other infectious diseases, identify opportunities for public-private partnerships, and assist the research community in designing and developing antiviral therapeutics. This report includes an overview of therapeutic approaches, individual panel summaries, and a summary of the discussions and perspectives on the challenges ahead for antiviral development.