Genesis and regulation of C-terminal cyclic imides from protein damage.

C-Terminal cyclic imides are posttranslational modifications that can arise from spontaneous intramolecular cleavage of asparagine or glutamine residues resulting in a form of irreversible protein damage. These protein damage events are recognized and removed by the E3 ligase substrate adapter cereblon (CRBN), indicating that these aging-related modifications may require cellular quality control mechanisms to prevent deleterious effects. However, the factors that determine protein or peptide susceptibility to C-terminal cyclic imide formation or their effect on protein stability have not been explored in detail.

Targeting pleckstrin-2/Akt signaling reduces proliferation in myeloproliferative neoplasm models.

Myeloproliferative neoplasms (MPNs) are characterized by the activated JAK2/STAT pathway. Pleckstrin-2 (Plek2) is a downstream target of the JAK2/STAT5 pathway and is overexpressed in patients with MPNs. We previously revealed that Plek2 plays critical roles in the pathogenesis of JAK2-mutated MPNs.

Synthesis and Evaluation of Noncovalent Naphthalene-Based KEAP1-NRF2 Inhibitors.

The oxidative stress response, gated by the protein-protein interaction of KEAP1 and NRF2, has garnered significant interest in the past decade. Misregulation in this pathway has been implicated in disease states such as multiple sclerosis, rheumatoid arthritis, and diabetic chronic wounds. Many of the known activators of NRF2 are electrophilic in nature and may operate through several biological pathways rather than solely through the activation of the oxidative stress response.

Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy.

Small molecules that directly target MYC and are also well tolerated in vivo will provide invaluable chemical probes and potential anti-cancer therapeutic agents. We developed a series of small-molecule MYC inhibitors that engage MYC inside cells, disrupt MYC/MAX dimers, and impair MYC-driven gene expression. The compounds enhance MYC phosphorylation on threonine-58, consequently increasing proteasome-mediated MYC degradation.

Palladium-catalyzed coupling reactions on functionalized 2-trifluoromethyl-4-chromenone scaffolds. Synthesis of highly functionalized trifluoromethyl-heterocycles.

The chromenone core is a ubiquitous group in biologically-active natural products and has been extensively used in organic synthesis. Fluorine derived compounds, including those with a trifluoromethyl group (-CF), have shown enhanced biological activities in numerous pharmaceuticals compared with their non-fluorinated analogs. We have found that 2-trifluoromethyl chromenones can be readily functionalized in the 8- and 7-positions, providing chromenones cores of high structural complexity which are excellent precursors for numerous trifluoromethyl-heterocycles.

Replacement of a Naphthalene Scaffold in Kelch-like ECH-Associated Protein 1 (KEAP1)/Nuclear Factor (Erythroid-derived 2)-like 2 (NRF2) Inhibitors.

Activators of nuclear factor-erythroid 2-related factor 2 (NRF2) could lead to promising therapeutics for prevention and treatment of oxidative stress and inflammatory disorders. Ubiquitination and subsequent degradation of the transcription factor NRF2 is mediated by Kelch-like ECH-associated protein-1 (KEAP1). Inhibition of the KEAP1/NRF2 interaction with small molecules leads to NRF2 activation.

Development of GLUT4-selective antagonists for multiple myeloma therapy.

Cancer cells consume more glucose to fuel metabolic programs fundamental to sustaining their survival, growth and proliferation. Among the fourteen SLC2A family members, GLUTs 1 and 4 are high-affinity glucose transporters. GLUT4 (SLC2A4) is highly expressed in muscle and adipose tissue.

Time-Gated Detection of Cystathionine γ-Lyase Activity and Inhibition with a Selective, Luminogenic Hydrogen Sulfide Sensor.

Herein, we report the design, synthesis, and characterization of a lanthanide complex-based probe for the time-gated luminescence detection of hydrogen sulfide (H S) in aqueous media. The probe's unique sensing mechanism relies on the selective reduction of azide to amine by sulfide, followed by intramolecular cyclization to form a quinolinone. The quinolinone is a sensitizer that absorbs near-UV light and transfers excitation energy to coordinated Tb or Eu ions to trigger a strong "turn-on" luminescence response with ms-scale lifetimes characteristic of lanthanide complexes.

Probing the structural requirements of non-electrophilic naphthalene-based Nrf2 activators.

Activation of the transcription factor Nrf2 has been posited to be a promising therapeutic strategy in a number of inflammatory and oxidative stress diseases due to its regulation of detoxifying enzymes. In this work, we have developed a comprehensive structure-activity relationship around a known, naphthalene-based non-electrophilic activator of Nrf2, and we report highly potent non-electrophilic activators of Nrf2. Computational docking analysis of a subset of the compound series demonstrates the importance of water molecule displacement for affinity, and the X-ray structure of di-amide 12e supports the computational analysis.

Desformylflustrabromine (dFBr) and [3H]dFBr-Labeled Binding Sites in a Nicotinic Acetylcholine Receptor.

Desformylflustrabromine (dFBr) is a positive allosteric modulator (PAM) of α4β2 and α2β2 nAChRs that, at concentrations >1 µM, also inhibits these receptors and α7 nAChRs. However, its interactions with muscle-type nAChRs have not been characterized, and the locations of its binding site(s) in any nAChR are not known. We report here that dFBr inhibits human muscle (αβεδ) and Torpedo (αβγδ) nAChR expressed in Xenopus oocytes with IC50 values of ∼ 1 μM.