PROTACs therapeutically target the polyglutamine androgen receptor in spinal and bulbar muscular atrophy models.

Spinal and bulbar muscular atrophy (SBMA) is a CAG/polyglutamine (polyQ) repeat expansion disorder in which the mutant androgen receptor (AR) protein triggers progressive degeneration of the neuromuscular system in men. As the misfolded polyQ AR is the proximal mediator of toxicity, therapeutic efforts have focused on targeting the mutant protein, but these prior efforts have met with limited success in SBMA patients. Here, we examine the efficacy of small molecule AR proteolysis-targeting chimera (PROTAC) degraders that rapidly and potently promote AR ubiquitination and degradation by the proteasome.

Discovery of a Novel Series of -Indolinone-Based Glutarimides as Highly Efficacious and Selective IKZF2 Molecular Glue Degraders.

Immunosuppressive Tregs, regulated by IKZF2 (Helios), promote tumor immune evasion and resistance to immune checkpoint therapies (ICTs). Targeting IKZF2 degradation offers a promising cancer immunotherapy approach. We developed a novel series of -indolinone-based glutarimides, identifying compound as a potent, selective IKZF2 degrader with >90% in Jurkat cells, outperforming benchmarks DKY709 and PVTX-405.

Streptococcus pneumoniae synchronizes the states of cell wall peptidoglycan acetylation and genome methylation by programmed DNA inversions.

Bacterial cell wall peptidoglycan (PG) consists of alternating β-(1,4) linked N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG). The C-6 hydroxyl group of NAM is acetylated by transmembrane O-acetyltransferases post PG biosynthesis in many pathogenic bacteria. This modification is important for bacterial resistance to lysozyme.

Thermionics in Topological Materials.

Thermionic emission is fundamental to many technologies and devices, including thermionic energy converters, X-ray tubes, scanning electron microscopes, and transmission electron microscopes. The discovery of topological materials, particularly graphene, has significantly advanced thermionics research. Thermionic emission in these materials deviates from the Richardson-Dushman equation due to their linear energy dispersion.

MD-4251: A First-in-Class Oral MDM2 Degrader Inducing Complete Tumor Regression with Single-Dose Administration.

MDM2 is a key negative regulator of the tumor suppressor p53 and an attractive target for cancer therapy. We report the discovery of MD-4251, the first orally efficacious MDM2 degrader developed using PROTAC technology. MD-4251 induces potent and rapid MDM2 degradation in RS4;11 cells (DC = 0.

STAT5 and STAT3 balance shapes dendritic cell function and tumour immunity.

Immune checkpoint blockade (ICB) has transformed cancer therapy. The efficacy of immunotherapy depends on dendritic cell-mediated tumour antigen presentation, T cell priming and activation. However, the relationship between the key transcription factors in dendritic cells and ICB efficacy remains unknown.

Discovery and Characterization of PVTX-321 as a Potent and Orally Bioavailable Estrogen Receptor Degrader for ER+/HER2- Breast Cancer.

Estrogen receptor α (ERα) is a key therapeutic target in ER+/HER2- breast cancer, but mutations drive resistance to endocrine therapies. Heterobifunctional degraders (HBDs) targeting ERα offer a promising strategy to overcome this resistance. Here, we report PVTX-321 (), a potent ER HBD derived from a novel spirocyclic cereblon ligand and an ERα binder.

Novel, potent, and orally bioavailable LSD1 inhibitors induce fetal hemoglobin synthesis in a sickle cell disease mouse model.

Small molecules that inhibit LSD1 (lysine-specific demethylase 1, KDM1A) have been shown to induce abundant fetal hemoglobin (HbF) levels in red blood cells both in vitro and in vivo, therefore potentially serving as potent and cost-effective therapeutics to treat the β-globinopathies, sickle cell disease (SCD), and β-thalassemia major (TM). However, most LSD1 inhibitors (LSD1is) that induce HbF in vivo are covalent and irreversible, which leads to adverse effects. In this study, we utilized structure-aided drug design to develop potent new reversible LSD1is, leading to robust γ-globin expression in vitro.

Development of PVTX-405 as a potent and highly selective molecular glue degrader of IKZF2 for cancer immunotherapy.

IKZF2 (Helios) is a transcription factor that is selectively expressed by Tregs and is essential for preserving the function and stability of Tregs in the tumor microenvironment (TME), where it suppresses the anti-tumor immune response. Targeted IKZF2 degradation by small molecules represents a promising strategy for the development of a new class of cancer immunotherapy. Herein, we describe the discovery of PVTX-405, a potent, effective, highly selective, and orally efficacious IKZF2 molecular glue degrader.

Albumin nanocomplex of BCL-2/xL inhibitor reduced platelet toxicity and improved anticancer efficacy in myeloproliferative neoplasm and lymphoma.

The clinical application of BCL-2/xL inhibitors for cancer treatment is limited by the on-target thrombocytopenia. Although APG-1252 was designed to mitigate this issue, platelet toxicity at higher doses in clinical trials restricts dose escalation for greater efficacy. We have developed albumin nanocomplexes of APG-1252 (Nano-1252) to reduce platelet toxicity while improving drug efficacy through enhancing drug delivery to lymphoid organs.

RAS mutation-specific signaling dynamics in response to paralog- and state- selective RAS inhibitors.

Unlabelled: A high therapeutic index (TI), balancing potent oncogenic signaling inhibition in tumor cells with minimal effects on normal cells, is critical for effective cancer therapies. Recent advances have introduced diverse RAS-targeting inhibitors, including mutant-specific inhibitors (e.g.

Terahertz waves promote Ca transport in the Ca2.1 channel.

Ca2.1 channels are the structural foundation for neurotransmitter transmission and other vital biological processes. If autoimmune-mediated reduction in presynaptic Ca2.

Multidimensional analyses identify genes of high priority for pancreatic cancer research.

Pancreatic ductal adenocarcinoma (PDAC) is a drug-resistant and lethal cancer. Identification of the genes that consistently show altered expression across patient cohorts can expose effective therapeutic targets and strategies. To identify such genes, we separately analyzed 5 human PDAC microarray datasets.

Discovery of SMD-3236: A Potent, Highly Selective and Efficacious SMARCA2 Degrader for the Treatment of SMARC4-Deficient Human Cancers.

SMARCA2 is an attractive synthetic lethal target in human cancers with mutated, inactivated SMARCA4. We report herein the discovery of highly potent and selective SMARCA2 PROTAC degraders, as exemplified by SMD-3236, which was designed using a new, high-affinity SMARCA ligand and a potent VHL-1 ligand. SMD-3236 achieves DC < 1 nM and > 95% against SMARCA2 and >2000-fold degradation selectivity over SMARCA4.

Discovery of High-Affinity SMARCA2/4 Bromodomain Ligands and Development of Potent and Exceptionally Selective SMARCA2 PROTAC Degraders.

In the SWI/SNF chromatin-remodeling complex, the mutually exclusive catalytic ATPase subunits SMARCA2 and SMARCA4 proteins have a synthetic-lethal relationship. Selectively targeting SMARCA2 for degradation is a promising and new therapeutic strategy for human cancers harboring inactivated mutated SMARCA4. In this study, we report the design, synthesis, and biological evaluation of novel SMARCA2/4 ligands and our subsequent design of PROTAC degraders using high-affinity SMARCA ligands and VHL-1 ligands.

The SpxA1-TenA toxin-antitoxin system regulates epigenetic variations of Streptococcus pneumoniae by targeting protein synthesis.

Human pathogen Streptococcus pneumoniae forms multiple epigenetically and phenotypically distinct intra-populations by invertase PsrA-driven inversions of DNA methyltransferase hsdS genes in the colony opacity-determinant (cod) locus. As manifested by phase switch between opaque and transparent colonies, different genome methylation patterns or epigenomes confer pathogenesis-associated traits, but it is unknown how the pathogen controls the hsdS inversion orientations. Here, we report our finding of the SpxA1-TenA toxin-antitoxin (TA) system that regulates the orientations of hsdS inversions, and thereby bacterial epigenome and associated traits (e.

Terahertz Wave Alleviates Comorbidity Anxiety in Pain by Reducing the Binding Capacity of Nanostructured Glutamate Molecules to GluA2.

Comorbid anxiety in chronic pain is clinically common, with a comorbidity rate of over 50%. The main treatments are based on pharmacological, interventional, and implantable approaches, which have limited efficacy and carry a risk of side effects. Here, we report a terahertz (THz, 10 Hz) wave stimulation (THS) technique, which exerts nonthermal, long-term modulatory effects on neuronal activity by reducing the binding between nano-sized glutamate molecules and GluA2, leading to the relief of pain and comorbid anxiety-like behaviors in mice.

Discovery of ERD-12310A as an Exceptionally Potent and Orally Efficacious PROTAC Degrader of Estrogen Receptor α (ERα).

Inhibition of estrogen receptor alpha (ERα) signaling is an established therapeutic approach for the treatment of ER-positive (ER+) breast cancers, but new therapeutic strategies are urgently needed to overcome clinical resistance. In the present study, we describe the discovery and extensive evaluation of ERD-12310A as an exceptionally potent and orally efficacious PROTAC degrader of ERα. ERD-12310A achieved a DC value of 47 pM and is 10 times more potent than ARV-471.

Proteolysis-targeting vaccines (PROTAVs) for robust combination immunotherapy of melanoma.

Protein/peptide subunit vaccines are promising to promote the tumor therapeutic efficacy of immune checkpoint blockade (ICB). However, current protein/peptide vaccines elicit limited antitumor T cell responses, leading to suboptimal therapeutic efficacy. Here, we present proteolysis-targeting vaccines (PROTAVs) that facilitate antigen proteolytic processing and cross-presentation to potentiate T cell responses for robust ICB combination immunotherapy of melanoma.

Discovery of Potent, Highly Selective, and Efficacious SMARCA2 Degraders.

We describe the identification of selective SMARCA2, VHL-based heterobifunctional degraders. Structurally novel indolo[1,2-]quinazolin-5(7)-one SMARCA bromodomain binders were optimized and then converted to SMARCA2 degraders by linking them to well-defined VHL ligands. Our exploration led to the discovery of potent and selective degraders of SMARCA2 over the SMARCA4 paralog, leading to potent and selective growth inhibition of SMARCA4 mutant versus wild type cell lines.

Discovery of MD-265: A Potent MDM2 Degrader That Achieves Complete Tumor Regression and Improves Long-Term Survival of Mice with Leukemia.

MDM2 has been pursued as an attractive therapeutic target for human cancers. Herein, we describe our discovery of MD-265 as a promising PROTAC MDM2 degrader and extensive and evaluations of its therapeutic potential and mechanism of action. MD-265 effectively depleted MDM2 protein in cancer cells at concentrations as low as 1 nM, leading to strong activation of p53 in cancer cells carrying wild-type p53.