ICB&DD Member's Research Highlights
Chronus Pharmaceuticals, Inc.
The Chronus Pharm. (Dr. Nicole Sampson, President) acquired a Phase 1 NIH/STTR grant for pediatric TB diagnostic feasibility work. LI BioHub REACH Proof of Concept grant was acquired, as well. Also, the Chronus Pharm. was selected as a StartupNY company by the NYS Governor’s Office. The CEO (Dr. Labros Meimetis) has been appointed.
MicroRid Technologies, Inc.
Dr. Maurizio Del Poeta founded “MicroRid Technologies Inc.” together with Brian McCarthy (CEO) and John Mallamo (CRO). The company is developing a new class of antifungal agents targeting the synthesis of fungal glucosylceramide with ICB&DD’s Discovery Chemistry
Lab. It is also currently developing a new ceramide synthase assay for the screening and identification of a specific fungal ceramide synthase inhibitor(s).
CuraMir Therapetuic, Inc.
CuraMir Therapeutic, Inc. was established in 2018 founded by Dr. Jingfang Ju. The mission of the company is to develop novel miRNA based cancer therapeutics to improve qualify and extend patient life. The company has licensed several miRNA platform
technologies from Stony Brook University.
As reported previously, Targagenix (CEO: James Eagan, Ph.D., MBA from SBU) licensed PUFA-Taxoid anticancer drug conjugates (Inventor: Dr. Ojima) from the Research Foundation of SUNY to develop these drug candidates. An NCI Contract was granted for the development of NE-PUFA-taxoids (nanoemulsion formulation of PUFAtaxoid conjugates) (Targagenix-SBU-Northeastern Univ. consortium). The project has been moving well and pre-IND feedback from FDA was encouraging and informative. Grant applications and VC fund acquisition have been actively ongoing.
Drug Discovery and Development
Dr. Nicole Sampson is developing azasteroids for treatment of tuberculosis. Cholesterol metabolism is important for persistence of Mycobacterium tuberculosis (Mtb) in mouse models of infection. Dr. Sampson’s group identified lead compounds that show excellent
antibacterial activity against M. tb. The inhibitor scaffold has high host in vivo stability, low host toxicity, and excellent host bioavailability. A lead compound has good bioavailability and is accumulated in the mouse lung, as well as shows no sign of
potential drug-drug interaction by in vitro tests. She assumed the President of Chronus Pharmaceuticals, Inc. Dr. Nicole Sampson is also developing a method for early detection of TB. The diagnosis rate of childhood TB is very low due to the lack of accurate diagnostic methods for children who cannot produce sputum samples. Her group identified a modified serum lipoprotein (MtLDL) that results from exposure to Mycobacterium tuberculosis, and have established an ELISA assay using anti-MtLDL mAbs that are being developed as a minimally invasive, robust, serum-based diagnostic tool to detect active tuberculosis. She obtained NIH REACH grant, as well as an STTR grant through Chronus Pharm. CPI-613, a novel “altered energy metabolism directed (AEMD)” anticancer drug invented
by Dr. Bingham, which was licensed to and being developed by the Cornerstone Pharmaceuticals, has reached Phase II human clinical trials for AML, MDS and solid tumors. Also, it is in Phase I and I/II for several indications and combinations, including
FOLFIRINOX (folic acid + 5-FU).
Development of NE-DHA-SBT-1214 by TargaGenix, Inc. (Dr. James Egan), based on Dr. Iwao Ojima’s invention of DHA-taxoids in combination with the unique nanoemulsion technology developed by Dr. Amiji (Northeastern Univ.), against CSC-initiated tumor xenografts are moving well. IND filing is in sight. Combination with anti-PDL-1 antibody exhibited a synergistic effect on highly challenging pancreatic cancer (PDAC) in vivo.
Dr. Jarrod French’s laboratory is developing novel Sts-1 inhibitors for deadly pathogen infections through
structure-based drug discovery approach. This project/invention has secured a drug
discovery grant from DOD, Fusion award from SOM and REACH grant
Dr. Kenneth Shroyer and Dr. Luisa Escobar-Hoyos discovered that keratin 17 (K17) protein and mRNA serve as excellent prognostic biomarkers
for patient survival, independent of tumor grade and stage in triple-negative breast,
cervical and pancreatic cancers. They also defined
binding domains that mediate K17 interaction with p27 and made K17 as druggable target. This team received the 2018 Pancreatic Cancer Action Network (PanCAN) Translational Research Award to further promote this project.
Dr. Jingfang Ju’s invention on novel miR-129 derivatives, bearing 5-FU in place of U units in the sequence show early promise as totally new approach to gene-based chemotherapy. A US Patent application was filed. Three more NTDs have been filed, which will lead to
patent applications. To pursue miRNA-based cancer therapeutics development, CuraMir Therapeutics, Inc. was founded.
Baldoxolone methyl (BARD), invented by
Dr. Tadashi Honda, is undergoing two Phase III studies: (i) for connective tissue disease-associated
pulmonary arterial hypertension (CTD-PAH) by Reata Pharmaceuticals, Inc. and (ii)
for diabetic nephropathy by Kyowa Hakko Kirin.
Both cases showed excellent Phase II and Phase IIb results. Reata is currently conducting a global Phase 3 clinical study on BARD in connective tissue disease associated PAH and a global Phase II/III clinical study in Alport syndrome.
A tricyclic cyanoenone, TBE-31, invented by Dr. Tadashi Honda, is an another Nrf2 activator, and has various features that BARD does not have. His team found that TBE-31 reverses high-fat diet and fructose-induced nonalcoholic steatohepatitis (NASH) in an Nrf2-
dependent manner. Since currently there are no treatments for NASH other than lifestyle changes, their findings offer hope to patients with NASH.
Dr. Maurizio Del Poeta’s laboratory has identified fungal ceramide synthase as novel drug target, and found a few hit compounds through HTP screening. Then he started collaboration with Dr. Iwao Ojima and ICB&DD’s Drug Discovery Lab. for hit-to-lead optimization. A large
size NIAID grant has been secured and three patent applications were filed and two WO patent applications were published. These compounds will be licensed to MicroRid Inc.
Development of novel fatty acid binding protein (FABP) inhibitors as new type of analgesic and anti-inflammatory agents, based on the lead compound, SB-FI-26, is moving well, a new PCT patent application for optimized compounds, exhibiting higher potency as well as sub-type selectivity, was filed. The FABP targets and FABP inhibitors were licensed to the Artelo Biosciences and preclinical drug development has been actively ongoing.
Dr. Peter Tonge developed [18F]F-PABA, a fluorine-18 analog of p-aminobenzoic acid. [18F]FPABA is able to defect and quantify bacterial infection in a soft tissue model of S. aureus infection using PET imaging. A Phase 1 STTR grant to evaluate [18F]F-PABA in a
preclinical model of prosthetic joint infection was obtained through Chronus Pharm.
Dr. Lori Chan identified Skp2 E3 ligase as excellent drug target in castration-resistant prostate cancer and a hit compound was identified by HTP assay. A collaboration with Dr. Jin Wang and Dr. Iwao Ojima for hit-to-lead optimization has led to the identification
of highly potent lead compounds, which will be further optimized.
Dr. Jarrod French’s laboratory is developing novel Sts-1 inhibitors for deadly pathogen infections through structure-based drug discovery approach. This project/invention has secured a drug discovery grant from DOD, Fusion award from SOM and REACH grant
from NIH. In addition, he received an NIH R21 grant on this drug discovery project.
Biomarkers and Targets
Keratin 17 was discovered in Dr. Kenneth Shroyer’s laboratory as diagnostic and prognostic biomarkers for cervical intraepithelial neoplasia (CIN) and squamous-cell carcinoma (SCC). Now, Keratin 17 was also validated as a highly sensitive and specific biomarker
for prognosis of pancreatic cancer. Two US Patent applications were filed and published (US20160187341A1, US20180340935A1). In addition, MR spectroscopy models were developed to evaluate metabolic properties impacted by keratin 17 in mouse xenograft
models of pancreatic cancer.
The miRNAs, miR192 and miR215, identified i n Dr. Jingfang Ju’s laboratory, would serve as new biomarkers in cancer diagnosis and prognosis in colorectal, gastric and endometrial cancers. These miRNAs would also provide excellent targets for novel anti-cancer therapeutics.
RNF8 E3 ligase was discovered by Dr. C.-H. Chan as a novel cancer stem cell (CSC)/EMT activator and drug target. Dr. Chan also discovered Skp2 E3 ligase as excellent drug target in castration-resistant prostate cancer.
Fatty acid binding proteins (FABPs) discovered by
Dr. Dale Deutsch’s laboratory are excellent targets for anti-inflammatory and analgesic drug discovery.
It has been shown by
ICB&DD Team (Deutsch, Kaczocha, Ojima, Rizzo and Li) that the inhibition of FABPs
increases the anandamide level, leading to potent anti-nociceptive effects. In addition, the inhibition of FABP5 and FABP7 have been shown to lead to tumor suppression, and thus FABP inhibitors can be developed for cancer therapy, as well.
FadA5, a flavin adenine dinucleotide and a thiolate from M. tuberculosis was identified
Dr. Nicole Sampson to be a new target for anti-TB drug discovery. Structural comparisons to human thiolases
revealed that it should be possible to target FadA5 specifically and the
steroid-bound structure provides a solid basis for the development of inhibitors against FadA5.
Dr. Jian Cao has found that the hemopexin domains of MMP9 and 14 are key functional components of these MMPs, which are required for cancer cell migration and invasion. Thus, these hemopexin domains would provide excellent targets for cancer chemotherapeutics to block cancer metastasis.
The V777L and other activated mutant forms of ErbB2 were identified by Dr. Todd Miller as potential target for drug discovery for breast cancer chemotherapy.
Biliverdin reductase B (BLVRB) is considered an excellent target for the development of drugs for oxidative stress-mediated diseases. Dr. Wadie Bahou and Dr. Jin Wang are screening inhibitors of BLVRB.
Cancer initiating cells (CICs), obtained by isolation from clinical samples and cultivation (
Dr. Galina Botchkina, colon and prostate cancers), have been successfully used to produce tumor xenografts
in nod-scid mice. These tumor xenografts are essential for drug
discovery targeting CICs.
Phosphoinositide 3-kinase (PI3K) isoform, p100, identified in Dr. Richard Lin’s laboratory, is a potential target for a novel therapy for the treatment of pancreatic cancer, either by targeted therapy or in combination with standard chemotherapy.
Serine hydrolases in the mycobacterial cell wall were identified in Dr. Jessica Seeliger’s laboratory as novel targets for possible intervention of TB by small-molecule inhibitors.
Basic Research Highlights
He P, Yang JW
, Yang VW, Bialkowska AB. Krüppel-like Factor 5, Increased in Pancreatic Ductal Adenocarcinoma, Promotes Proliferation,
Acinar-to-Ductal Metaplasia, Pancreatic Intraepithelial Neoplasia, and Tumor Growth
in Mice. Gastroenterology,
Abedini A., Cao P., Plesner A., Zhang J. H., He M. L., Derk J., Patil S. A., Rosario
R., Lornier J., Song F., Koh H., Li H. L.,
Raleigh D. P., Schmidt, A. M. RAGE binds preamyloid IAPP intermediates and mediates pancreatic
beta cell proteotoxicity. J. Clin.
Invest., 2018, 128, 682-698.
Laptenok SP, Gil AA, Hall CR, Lukacs A, Iuliano JN, Jones GA, Greetham GM, Donaldson
P, Miyawaki A, Tonge PJ, Meech SR. Infrared spectroscopy reveals multistep multi-timescale
photoactivation in the photoconvertible protein archetype dronpa.
Nat. Chem. 2018; 10: 845-852.
Zheng, W.; Morales-Rivera, C. A.; Lee, J. W.; Liu, P.; Ngai, M.-Y. Catalytic C−H Trifluoromethoxylation of Arenes and Heteroarenes. Angew. Chem. Int. Ed . 2018; 57: 9645-9649.
Haj-Dahmane S, Shen RY, Elmes MW, Studholme K, Kanjiya MP, Bogdan D, Thanos PK, Miyauchi JT, Tsirka SE, Deutsch DG, Kaczocha M. Fatty-acid-binding protein 5 controls retrograde endocannabinoid signaling at central glutamate synapses. Proc. Natl. Acad. Sci. U S A. 2018;115(13): 3482-3487.
Seeliger MA. More Diversity Yields a Clearer Picture into the Architecture of the Protein Kinase Domain. Cell Syst. 2018;7(4): 356-357.
Munshi MA, Gardin JM, Singh A, Luberto C, Rieger R, Bouklas T, Fries BC, Del Poeta M. The role of ceramide synthases in the pathogenesis of Cryptococcus neoformans. Cell Rep. 2018; 22(6): 1392-1400.
Bogenhagen, D.F., Ostermeyer-Fay, A., Haley, J.D., Garcia-Diaz, M. Kinetics and Mechanism of Mammalian Mitochondrial Ribosome Assembly. Cell Rep. 2018; 22(7):1935-1944.
Fernandes CM, Goldman GH, Del Poeta M. Biological Roles Played by Sphingolipids in Dimorphic and Filamentous Fungi. MBio. 2018; 9(3): e00642-18.
Lu H, Iuliano JN; Tonge PJ. Structure-kinetic relationships that control the residence time of drug-target complexes: insights from molecular structure and dynamics. Curr. Opin. Chem. Biol. 2018; 44: 101-109.
Lee, K. N.; Spiegowski, D. N.; Lee, J. W.; Lim, S.; Zhao, F;
Ngai, M.-Y. Transition-Metal-Free C–H Amidation and Chlorination: Synthesis of N/N′-Mono-Substituted Imidazopyridin-2ones
from N-Pyridyl-N-Hydroxylamine Intermediates. Chem. Commun.
2018; 54: 6935-6938.
Zhang, J., Li, G., Sampson, N. S. Incorporation of large cycloalkene rings into alternating copolymers allows control of glass transition and hydrophobicity. ACS Macro. Lett. 2018;7; 1068–1072.
N. Van Skike, N. K. Minkah, C.H. Hogan, G. Wu, P. T. Benziger, M. Kara, S. A. Tibetts, D. Kim-Hozapfel, J. B. French, D. G. Oldenburg, D. W. White, L. T. Krug. Viral FGARAT ORF75A promotes the specific infectivity of virus particles and gammaherpesvirus pathogenesis in mice. PLoS Pathogens, 2018; 14(2): e1006843.
T. Koga, D. A. Barkley, M. Nagao, T. Taniguchi, J.-M. Y. Carrillo, B. G. Sumpter, T. Masui, H. Kishimoto, M. Koga, J. G. Rudick, M. K. Endoh. “Interphase structures and dynamics near nanofiller surfaces in polymer solutions” Macromolecules, 2018; 51(23): 9462–9470.
Li, G., Sampson, N. S. Alternating Ring-Opening Metathesis Polymerization (AROMP) of Hydrophobic and Hydrophilic Monomers Provides Oligomers with Side-Chain Sequence Control. Macromolecules, 2018; 51: 3932–3940.
Chen X, Gaglione R, Leong T, Bednor L, de Los Santos T, Luk E, Airola M, Hollingsworth NM. Mek1 coordinates meiotic progression with DNA break repair by directly phosphorylating and inhibiting the yeast pachytene exit regulator Ndt80 PLoS Genetics, 2018;14(11): e1007832
Wu N, Fesler, Liu H, Ju J. Development of novel miR-129 mimics with enhanced efficacy to eliminate chemoresistant colon cancer stem cells. Oncotarget, 2018, 9(10): 8887-8897.
D. A. Barkley, S. U. Han, T. Koga, J. G. Rudick. “Peptide-Dendron Hybrids that Adopt Sequence-Encoded β-Sheet Conformations.” Polym. Chem. 2018; 9(40): 4994–5001.
Akter R., Bower R., Abedini A, Schmidt A. M., Hay D. L.
Raleigh D. P. Amyloidogencity, Cytotoxicity, and Receptor Activity of Bovine Amylin: Implications
for Xenobiotic Transplantation and the Design of Nontoxic Amylin Variant. ACS Chem.
Hossain, S.; Heckler, I.; Boon, E.M. Discovery of a nitric oxide responsive quorum sensing circuit in Vibrio cholera. ACS Chem. Biol., 2018, 13, 1964–1969.
Preston, A. N., Farr, J. D., O’Neill, B. K., Thompson, K. K., Tsirka, S. E., Laughlin, S. T. Visualizing the brain’s astrocytes with diverse chemical scaffolds. ACS Chem. Biol., 2018; 13: 1493–1498.
O’Neill, B.K.; Laughlin, S. T. Neuronal calcium recording with an engineered TEV protease. ACS Chem. Biol. 2018; 13: 1159–1164.
Paung Y, Seeliger MA. KA1 Domains: Unity in Mechanistic Diversity. Structure, 2018; 26(8): 1045-1047.
S. Yan, M. W. Elmes, S. Tong, K. Hu, M. Awwa, G. Y. H. Teng, Y. Jing, M. Freitag, Q. Gan, T. Clement, L. Wei, J. M. Sweeney, O. M. Joseph, G. S. Carbonetti, L. Wang, J. Falcone, N. Smietalo, Y. Zhou, B. Ralph, H.-C. Hsu, H. Li, R. C. Rizzo, D. G. Deutsch, M. Kaczocha, I. Ojima. SAR Studies on Truxillic Acid Mono Esters as a New Class of Antinociceptive Agents, Targeting Fatty Acid Binding Proteins. Eur. J. Med. Chem., 2018; 154: 233-252.
C. Lazzarini, K. Haranahalli, R. Rieger, H. Krishna Ananthula, P. B. Desai, A. Ashbaugh, M. J. Linke, M. T. Cushion, B. Ruzsicska, J. Haley, I. Ojima, M. Del Poeta, Acylhydrazones as antifungal agents targeting the synthesis of fungal sphingolipids. Antimicrob. Agents Chemother. 2018; 62(5): e00156-18.
Bryan, A; Del Poeta M. Sphingosine-1-phosphate receptor and innate immunity. Cell. Microbiol. 2018; 20(5): e12836.
Ganapathy, U.S., Bai, L., Wei, L., Eckartt, K.A., Lett, C.M., Previti, M.L., Carrico, I.S., Seeliger, J.C. Compartment-Specific Labeling of Bacterial Periplasmic Proteins by Peroxidase-Mediated Biotinylation. ACS Infect Dis. 2018; 4: 918-925.
Stenzoski N. E., Luang, B., Holehouse A.S., Raleigh, D. P. The Unfolded State of the CTerminal Domain of L9 Expands at Low but Not at Elevated Temperatures. Biophysical J. 2018; 115: 655-663.
Suga H, Miller WT. Src signaling in a low-complexity unicellular kinome. Sci Rep. 2018; 8(1):5362.
Naidu, S. D.; Muramatsu, A.; Saito, R.; Asami, S.; Honda, T.; Hosoya, T.; Ito, K.; Yamamoto, M.; Suzuki, T.; Dinkova-Kostova, A. T. C151 in Keap1 is the main cysteine sensor for the cyanoenone class of NRF2 activators, irrespective of molecular size or shape. Sci. Rep. 2018; 8: 8037.
Bhalla K., Jaber S., Nahid M.N., Underwood K., Beheshti A., Landon A., Bhandary B., Bastain
P., Evens A.M.,
Haley J., Polster B., Gartenhaus R.B. "Role of hypoxia in Diffuse Large B-cell Lymphoma:
Metabolic repression and selective translation of HK2
facilitates development of DLBCL". Sci Rep. 2018; 8(1):744-759.
T. Wang, Y. Zhang, L. Wei, Y. G. Teng, T. Honda, I. Ojima, Design, Synthesis and Biological Evaluations of Asymmetric Bow-Tie PAMAM Dendrimer-based Conjugates for Tumor-Targeted Drug Delivery. ACS Omega, 2018; 3(4): 3717–3736.
Li, Z., N. Nesbitt, L. Malone, D. Gnatenko, W. Wu, D. Wang, W. Zhu, G. Girnun, and W. Bahou. Heme degradation enzyme biliverdin IX reductase is required for stem cell glutamine metabolism. Biochem. J. 2018; 475: 1211-23.
Nesbitt, N., X. Zhang, Z. Li, J. Manso, W-Y Yen, L. Malone, J. Ripoli-Rozada, P.J.B. Pereira,
J. Wang, and
W. Bahou. Identification of biliverdin IXβ reductase inhibitors with nanomolar potency using
in silico and crystallographic models. J. Biol. Chem.
293:5431-46. [journal Cover]
I. Ojima, X. Wang, Y. Jin, C. Wang, Quest for Efficacious Next-Generation Taxoid Anticancer Agents and Their Tumor-Targeted Delivery. J. Nat. Prod. 2018; 81: 703-721 (2018) (ACS Editor’s Choice Article)
Nandan MO, Bialkowska AB, Yang VW. KLF5 mediates the hyper-proliferative phenotype of the intestinal epithelium in mice with intestine-specific endogenous KRas ( G12D) expression. Am J Cancer Res. 2018; 8(4): 723-731.
Guo S, Fesler A, Wang H, Ju J. microRNA based prognostic biomarkers in pancreatic cancer. Biomarker Res. 2018; 6:18.
H. Li, C. Guo, D. Kim-Holzapfel, W. Li, Y. Altshuller, B. Shroeder, W. Liu, Y. Meng, J. B. French, K. Takemaru, M. A. Frohman, S. Jia, Volumetric live-cell imaging using highresolution light-field microscopy. Biomed. Opt. Express, 2018; 10(1): 29-49.
Ganesan R, Henkels KM, Wrenshall LE, Kanaho Y, Paolo GD,
Frohman MA, Gomez-Cambronero J. Oxidized LDL phagocytosis during foam cell formation in atherosclerotic plaques
relies on a PLD2-CD36 functional interdependence. J. Leukoc. Biol.
Bacon, B.; Liu, Y .; Kincaid, J.; Boon, E.M. Spectral characterization of a novel NOsensing protein in bacteria: NosP. Biochemistry, 2018; 57: 6187-6200.
J. N. Iuliano, A. A. Gil, S. P. Laptenok, C. R. Hall, J. Tolentino Collado, A. Lukacs, S. A. Hag Ahmed, J. Abyad, T. Daryaee, G. M. Greetham, I. B. Sazanovich, B. Illarionov, A. Bacher, M. Fischer, M. Towrie, J. B. French, S. R. Meech, P. J. Tonge. Variation in LOV photoreceptor activation dynamics probed by time resolved infrared spectroscopy. Biochemistry. 2018; 57(5): 620-630.
Guo J, Collins S, Miller WT, Rizzo RC. Identification of a Water-Coordinating HER2 Inhibitor by Virtual Screening Using Similarity-Based Scoring. Biochemistry, 2018; 57(32):4934-4951.
Albanese SK, Parton DL, Işık M, Rodríguez-Laureano L, Hanson SM, Behr JM, Gradia S,
Jeans C, Levinson NM,
Seeliger MA, Chodera JD. An Open Library of Human Kinase Domain Constructs for Automated Bacterial
Gadbery, J.; Sampson, N. S. Use of an Isotope-Coded Mass Tag (ICMT) Method to Determine the Orientation of Cholesterol Oxidase on Model Membranes. Biochemistry, 2018; 57: 5370-5378
Regenbogen E, Mo M, Romeiser J, Shroyer ALW, Escobar-Hoyos LF, Burke S, Shroyer KR. Elevated expression of keratin 17 in oropharyngeal squamous cell carcinoma is associated with decreased survival. Head Neck 2018; 40:1788-1798.