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PNAS Papers on Small Molecule From Soil Bacteria, Circulating Tumor Cell Chip, More

Editor's Note: Some of the articles described below are not yet available at the PNAS site, but they are scheduled to be posted some time this week.

Researchers from California's Warp Drive Bio, Harvard University, and elsewhere report on a rapamycin family small molecule called WDB002, produced by Streptomycetes soil bacteria, that appears to bind to and inhibit a 'flat surface' human centrosomal protein 250 (CEP250) — a protein believed to interact with the SARS-CoV-2 protein Nsp13. Starting with some 135,000 available bacterial genomes, the team searched for biosynthetic gene clusters coding for compounds related to the rapamycin and FK506 natural products, focusing in on S. malaysiensis DSM41697 strain gene cluster that codes for cell-permeable, rapamycin/FK506-related small molecules. Within that cluster, the authors note, the WDB002 compound bound CEP250 in concert with the FK506-binding protein (FKBP), leading to altered CEP250 activity. "The present results provoke a thorough reevaluation and expansion of protein targets that should be considered druggable," they write, "and suggest that FKBP-assisted targeting can enable even the flattest of protein targets to be productively engaged by orally active small molecules."

For another paper slated to appear in PNAS this week, a Massachusetts team describes its ultrahigh-throughput microfluidics approach for capturing tumor cells out of circulation in the blood. With a magnetic sorting strategy to help remove antibody-tagged leukocyte white blood cells in the soft iron-filled channel system, the researchers say, the CTC-iChip method makes it possible to enrich for circulating tumor cells (CTCs) in mononuclear cell collections. "The negative depletion of antibody-tagged leukocytes enables isolation of potentially viable CTCs without bias for expression of specific tumor epitopes, making this platform applicable to all solid tumors," they write, noting that combining the CTC-iChip with clinical leukapheresis methods for concentrating white blood cells "will enable non-invasive sampling of cancer cells in sufficient numbers for clinical applications, ranging from real-time pharmacokinetic monitoring of drug response to tissue-of-origin determination in early-stage cancer screening."

Investigators from China and the US share findings from a chemical library screen aimed at untangling processes behind gene silencing at chromatin sites near DNA double-strand breaks. Based on chemical screen involving 760 compounds that inhibit kinase enzymes, or the 'human kinome' — in combination with DNA damage, fluorescence imaging, small interference RNA silencing, and other experiments — the team saw signs that such transcriptional pausing stems from a network centered on a DNA damage-responsive kinase enzyme called DYRK1B that, in turn, targets a histone methyltransferase enzyme known as EHMT2. "Together," the authors report, "our findings unveil the DYRK1B signaling network as a key branch of mammalian DNA damage response circuitries, and establish the DYRK1B-EHMT2 axis as an effector that coordinates [double-strand break] repair on transcribed chromatin."