Abstract: New synthetic methods to provide access to previously unexplored functionality at the C8 position of substituted imidazo[5,1-d][1,2,3,5]tetrazines of Formula I. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 hours), a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent was derived. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ, leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM.

Abstract: The post-translational modification (PTM) and signaling molecule poly(ADP-ribose) (PAR) has an impact on diverse biological processes. PTM is regulated by a series of ADP-ribosyl glycohydrolases (PARG enzymes) that cleave polymers and/or liberate monomers from their protein targets. Disclosed herein is a substrate for monitoring PARG activity, TFMU-ADPr, which directly reports on total PAR hydrolase activity via release of a fluorophore; this substrate has excellent reactivity, generality, stability, and usability. A second substrate, TFMU-IDPr, selectively reports on PARG activity only from the enzyme ARH3. Use of these probes in whole-cell lysate experiments has revealed a mechanism by which ARH3 is inhibited by cholera toxin. TFMU-ADPr and TFMU-IDPr are versatile tools for assessing small-molecule inhibitors in vitro and probing the regulation of ADP-ribosyl catabolic enzymes.

Abstract: Small molecule inhibitors of the localization of lipoprotein CDE (LolCDE) complex that is found in the membrane of bacteria. Searches for suitable candidates for the LolCDE complex led to the discovery of an inhibitor named lolamycin. Lolamycin specifically targets Gram-negative bacteria such as Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Salmonella typhimurium, and is selective over Gram-negative and Gram-positive commensal bacteria, thereby avoiding perturbation of the gut microbiome.

Abstract: Disclosed herein are antibacterial compounds that accumulate in Gram-negative bacteria, methods of preparing the compounds, and methods of using the compounds to inhibit or kill microbes, and methods of treating microbial infections, such as Gram-negative bacterial infections. Compounds selected for conversion to potential Gram-negative antibacterial compounds were identified based on compounds having low globularity and low flexibility. Amine substituents were then strategically added to the selected compounds to provide compounds having antibacterial activity against Gram-negative bacteria.

Abstract: A set of small molecules ER? biomodulators that kill therapy-resistant ER? positive breast, ovarian, and endometrial cancer cells. These small molecules have increased therapeutic potential because of an increased ability to kill therapy-resistant breast cancer cells compared to BHPI and other conventional therapies (endocrine therapies, tamoxifen and fulvestrant/ICI). The new compounds do not only inhibit proliferation of the cancer cells but actually kills them, which prevents reactivation of tumors years later.

Abstract: The discovery of mutant or fusion kinases that drive oncogenesis, and the subsequent approval of specific inhibitors for these enzymes, has been instrumental in the management of some cancers. However, acquired resistance remains a significant problem in the clinic, limiting the long-term effectiveness of most of these drugs. Herein is demonstrated a strategy to overcome this resistance through drug-induced MEK cleavage (via direct procaspase-3 activation) combined with targeted kinase inhibition. This combination effect is shown to be general across diverse tumor histologies (melanoma, lung cancer, and leukemia) and driver mutations (mutant BRAF or EGFR, fusion kinases EML4-ALK and BCR-ABL). Caspase-3-mediated degradation of MEK kinases results in sustained pathway inhibition and substantially delayed or eliminated resistance in cancer cells in a manner superior to combinations with MEK inhibitors.

Abstract: The technology disclosed herein provides (4aR,4bS,6aS,9aS,9bS)-1-(4-chlorobenzyl)-4a,6a-dimethyl-3,4,4a,6,6a,8,9,9a,9b,10-decahydro-1H-indeno[5,4-f]quinoline-2,5,7(4bH)-trione, identified as compound IB:10:D, and related compounds. Compound IB:10:D was discovered though screening a compound library for inhibitors of the enzyme SULT2B1b. This enzyme, which produces the product cholesterol sulfate, is overexpressed in cancer. The product acts as an immunosuppressant that results in suppression of the immune system's ability to clear tumor cells. Compounds related to IB:10:D were synthesized and shown to inhibit production of cholesterol sulfate. The discovered inhibitors of SULT2B1b provide new compounds and methods for immunotherapy and cancer treatment.

Abstract: Synergistic drug combinations with the small molecule PAC-1 against uveal or cutaneous melanoma. There are no current targeted drug treatments for the mutations associated with uveal melanoma. Despite primary radiation or surgical therapy, up to 50% of patients eventually develop metastatic disease, for which there is no standard therapy nor treatment shown to improve overall survival. Drug combinations with PAC-1 allow the use of lower dosages of this compound that result in cancer cell death in uveal melanoma. Drug combinations of PAC-1 with the kinase inhibitor entrectinib have shown a synergistic effect against uveal melanoma cell lines. Specifically, PAC-1 and entrectinib are synergistic against wild-type and mutant uveal melanoma cell lines (e.g., GNAQ and GNA11).

Abstract: A FabI inhibitor called fabimycin that has impressive activity against >200 clinical isolates of E. coli, K. pneumoniae, and A. baumannii. Fabimycin has activity in multiple mouse models of infection caused by Gram-negative bacteria, including a model of urinary tract infection. Fabimycin has translational promise, and its discovery provides data indicating that antibiotics whose spectrum of activity is restricted to Gram-positive bacteria can be systematically modified to accumulate in Gram-negative bacteria and be effective against these problematic pathogens.

Abstract: New synthetic methods to provide access to previously unexplored functionality at the C8 position of substituted imidazo[5,1-d][1,2,3,5]tetrazines of Formula I. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 hours), a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent was derived. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ, leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM.

Abstract: Disclosed herein are antibacterial compounds that accumulate in Gram-negative bacteria, methods of preparing the compounds, and methods of using the compounds to inhibit or kill microbes, and methods of treating microbial infections, such as Gram-negative bacterial infections. Compounds selected for conversion to potential Gram-negative antibacterial compounds were identified based on compounds having low globularity and low flexibility. Amine substituents were then strategically added to the selected compounds to provide compounds having antibacterial activity against Gram-negative bacteria.

Abstract: Novel Fusidic Acid (FA) based compounds that have equivalent potency against clinical isolates of Staphylococcus aureus (S. aureus) and Enterococcus faecium (E. faecium) as well as an improved resistance profile in vitro when compared to FA. Importantly, the new compounds display efficacy against a FA-resistant strain of Staphylococcus aureus in a soft-tissue murine infection model. This disclosure delineates the structural features of FA necessary for potent antibiotic activity and demonstrates that the resistance profile can be improved for this scaffold and target.

Abstract: Compositions and methods for the induction of cell death, for example, cancer cell death. Combinations of compounds and related methods of use are disclosed, including the use of compounds in therapy for the treatment of cancer and selective induction of apoptosis in cells. The disclosed drug combinations can have lower neurotoxicity effects than other cancer therapies that achieve the same or similar therapeutic effect.

Abstract: A saliva-based testing method that bypasses the need for RNA isolation/purification is described herein. In experiments with inactivated SARS-CoV-2 virus spiked into saliva, this method has a limit of detection of 500-1000 viral particles per mL, rivalling the standard NP swab method. Initial studies showed excellent performance with 100 clinical samples. This saliva-based process is operationally simple, utilizes readily available materials, and can be easily implemented by existing testing sites thus allowing for high-throughput, rapid, and repeat testing of large populations.

Abstract: Disclosed are novel compounds that accumulate in Gram-negative bacteria. Also disclosed are method of antimicrobial treatment using the compounds.

Abstract: The invention provides compositions and methods for the induction of cell death, for example, cancer cell death. Combinations of compounds and related methods of use are disclosed, including the use of compounds in therapy for the treatment of cancer and selective induction of apoptosis in cells. The disclosed drug combinations can have lower neurotoxicity effects than other compounds and combinations of compounds.

Abstract: Small molecule ER? biomodulators that kill therapy-resistant ERa positive breast, ovarian, and endometrial cancer cells are disclosed. In one embodiment, the small molecule biomodulator has increased therapeutic utility because of an increased ability to kill therapy-resistant cancer cells compared to BHPI and other conventional therapies (endocrine therapies, tamoxifen, and fulvestrant/ICI). The small molecule biomodulators not only inhibit proliferation of the cancer cells but kills them, which prevents reactivation of tumors years later. Compounds of the invention, such as ErSO-DFP, are effective for treating ERa positive cancers such as breast cancer, ovarian cancer, uterine cancer, cervical carcinoma, endometrial cancer, and the like.

Abstract: The invention provides compositions and methods for the induction of cell death, for example, cancer cell death. Combinations of compounds and related methods of use are disclosed, including the use of compounds in therapy for the treatment of cancer and selective induction of apoptosis in cells. The disclosed drug combinations can have lower neurotoxicity effects than other compounds and combinations of compounds.

Abstract: Disclosed herein are antibacterial compounds that accumulate in Gram-negative bacteria, methods of preparing the compounds, and methods of using the compounds to inhibit or kill microbes, and methods of treating microbial infections, such as Gram-negative bacterial infections. Compounds selected for conversion to potential Gram-negative antibacterial compounds were identified based on compounds having low globularity and low flexibility. Amine substituents were then strategically added to the selected compounds to provide compounds having antibacterial activity against Gram-negative bacteria.

Abstract: New synthetic methods to provide access to previously unexplored functionality at the C8 position of substituted imidazo[5,1-d][1,2,3,5]tetrazines of Formula I. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 hours), a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent was derived. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ, leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM.