BLOOD CELL TECHNOLOGIES, LLC

631-751-3467

wfb7777@gmail.com

WADIE BAHOU

Self-Certified Small Disadvantaged Business

P1886617

HH9LT9M9B3N4

76LR5

2026-01-19

2025-01-21

2014-08-07

76LR5

Obsolete

Non-Manufacturer

2024-03-14

2025-03-12

WADIE F.. BAHOU

+1 631-751-3467

2023-09-14

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Department of Health and Human Services

DEVELOPMENT OF A NEW CLASS OF BLVRB-TARGETED REDOX THERAPEUTICS IN BREAST CANCER - SUMMARY ENHANCED METABOLIC AND MITOCHONDRIAL ACTIVITY INHERENT IN ACTIVELY PROLIFERATING CANCER CELLS GENERATES AN EXCESSIVE AMOUNT OF REACTIVE OXYGEN SPECIES (ROS), ASSOCIATED WITH INTRACELLULAR REDOX IMBALANCE THAT IMPACTS CELLULAR VIABILITY.TO SURVIVE CHRONIC OXIDATIVE STRESS, CANCER CELLS EVOLVE TO ACTIVATE SCAVENGING/ANTI-OXIDANT ENZYMES TO RESTORE REDOX BALANCE. THIS DIFFERENTIAL ACTIVATION OF ANTIOXIDANT PATHWAYS COMPARED TO NORMAL CELLS PROVIDES A THERAPEUTIC WINDOW FOR NOVEL CELLULAR TARGETS. MOREOVER, THE EFFECTS OF CHEMO- AND RADIOTHERAPY (IN PART) ARE ATTRIBUTED TO OXIDATIVE STRESS THAT CAUSES IRREVERSIBLE OXIDATIVE DAMAGE AND CELL DEATH, AND ACTIVATION OF REDOX-REGULATING PATHWAYS IS THOUGHT TO PROMOTE RESISTANCE TO SUCH THERAPIES. THE OBLIGATORY DEPENDENCE OF CANCER CELLS ON ANTIOXIDANT DEFENSE PATHWAYS AS A FUNDAMENTAL PRO-SURVIVAL MECHANISM SUGGESTS THE BROAD TRANSLATIONAL UTILITY OF THEIR TARGETING IN BREAST CANCER. MODULATION OF REDOX-ADAPTATION MECHANISMS REPRESENTS A FEASIBLE STRATEGY TO ERADICATE CANCER CELLS AND/OR RESTORE CHEMOSENSITIVITY TO CONVENTIONAL THERAPIES. FOR THE FIRST TIME, WE IDENTIFIED THE HEME (FE2+-PROTOPORPHYRIN IX) CATABOLIC ENZYME BLVRB (BILIVERDIN IXSS REDUCTASE) AS A NEW CELLULAR TARGET IN BREAST CANCER. WE DEMONSTRATED THE REQUISITE AND NON-REDUNDANT PRO- SURVIVAL ANTIOXIDANT FUNCTION OF BLVRB IN BREAST CANCER CELLS, COUPLED WITH THERAPY RESISTANCE AND POOR OUTCOMES IN BREAST CANCER PATIENTS. THE PRIMARY HYPOTHESIS OF THIS APPLICATION IS THAT BLVRB FUNCTIONS IN A REDOX- REGULATED PATHWAY OF ANTIOXIDANT HANDLING AND CYTOPROTECTION IN BREAST CANCER CELLS. THE SECONDARY HYPOTHESIS IS THAT BLVRB-SELECTIVE INHIBITOR(S) MAY BE DEVELOPED AS A NOVEL AND POTENTIALLY NON-TOXIC STRATEGY FOR BREAST CANCER TREATMENT WITH MINIMAL PREDICTED OFF-TARGET EFFECTS IN NORMAL CELLS. USING (1) BLVRB/INHIBITOR CO-CRYSTAL STRUCTURES, (2) COMPUTATIONAL RMSD MATRICES FOR SARS, AND (3) EXTENSIVE ADME/T AND PK STUDIES, WE IDENTIFIED TWO LEAD COMPOUNDS WITH EXCELLENT BIOAVAILABILITY AND ORAL PK CHARACTERISTICS THAT SELECTIVELY BLOCK BLVRB REDOX COUPLING. THE OBJECTIVES OF THIS PROPOSAL ARE (1) TO EXTEND INITIAL PROOF-OF-PRINCIPLE STUDIES FOR BLVRB PRE-CLINICAL TARGET VALIDATION USING IN VIVO BREAST CANCER MODELS, AND (2) TO CHARACTERIZE FIRST-IN-CLASS BLVRB-SELECTIVE INHIBITORS FOR IN VITRO AND IN VIVO EFFICACY. STUDY DESIGN: WE WILL APPLY IN VIVO GENETIC MODELS FOR TARGET VALIDATION, SIMULTANEOUSLY ADDRESSING REDOX-DEPENDENT MECHANISMS BY GENE COMPLEMENTATION STUDIES USING BLVRB+/+ AND BLVRB-/- BREAST CANCER ISOGENIC LINES: (1) TO CONFIRM REQUISITE FUNCTIONS IN TUMOR GROWTH AND METASTATIC BURDEN; (2) TO ESTABLISH REDOX-DEPENDENT PHENOTYPE (AIM 1). AIM 2 WILL VALIDATE THE PRE-CLINICAL EFFICACY OF LEAD COMPOUNDS USING WELL-ESTABLISHED PHENOTYPIC READ-OUTS IN VITRO AND IN ORTHOTOPIC BREAST CANCER IMPLANTATION MODELS. WE WILL ALSO ADDRESS SYNTHETIC LETHALITY BLVRB INHIBITORS WITH STANDARD-OF-CARE CHEMOTHERAPY IN VIVO. IMPACT: IF SUCCESSFUL, THE PROPOSED WORK WOULD BE FIRST-IN-CLASS PRE-CLINICAL VALIDATION OF REDOX INHIBITORS IN BREAST CANCER, REPRESENTING A POTENTIAL PARADIGM SHIFT FOR CANCER THERAPEUTICS.

285200.00

0.00

0.00

2021-08-06

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Department of Health and Human Services

OPTIMIZATION OF BILIVERDIN IX? REDUCTASE REDOX INHIBITORS AS NOVEL REAGENTS FOR ENHANCING PLATELET PRODUCTION - PROGRAM DIRECTOR/PRINCIPAL INVESTIGATOR (LAST, FIRST, MIDDLE): NESBITT, NATASHA M.. PROJECT SUMMARY/ABSTRACT THIS PHASE II SBIR PROPOSAL WILL SUPPORT OUR ONGOING DRUG DISCOVERY PROGRAM DESIGNED TO DEVELOP AND VALIDATE SMALL MOLECULE INHIBITORS OF A NOVEL DRUG TARGET REGULATING PLATELET PRODUCTION IN HUMANS. THE SCOPE OF WORK BUILDS ON STRONG GENETIC AND BIOCHEMICAL EVIDENCE LINKING REDOX-DEPENDENT ENZYMATIC ACTIVITY OF BILIVERDIN IX REDUCTASE (BLVRB) IN A PREVIOUSLY-UNCHARACTERIZED REGULATORY PATHWAY OF MEGAKARYOCYTE DEVELOPMENT AND ENHANCED PLATELET PRODUCTION. IN SILICO VIRTUAL SCREENING WITH OUR NOVEL SCORING FUNCTION LED TO THE IDENTIFICATION OF ~20 COMPOUNDS PREDICTED TO INHIBIT THE REDOX ACTIVITY OF BLVRB. BIOCHEMICAL AND CELL-BASED ASSAYS VALIDATED FOUR OF THESE COMPOUNDS AS POTENT INHIBITORS OF THE ENZYME. A COMPLEMENTARY CRYSTALLOGRAPHIC ASSAY LED TO THE IDENTIFICATION OF TWO ADDITIONAL COMPOUNDS WITH INCREASED POTENCY TOWARDS BLVRB. WE WILL EMPLOY MEDICINAL AND COMPUTATIONAL CHEMISTRY TO OPTIMIZE OUR HIT COMPOUNDS TO DEVELOP LEAD COMPOUNDS WITH IMPROVED POTENCY AND SELECTIVITY FOR BLVRB. THESE COMPOUNDS WILL BE FURTHER CHARACTERIZED USING IN VITRO HEMATOPOIETIC ASSAYS AND FOLLOW UP IN VIVO ANIMAL STUDIES TO SHOW IMPROVED EFFICACY IN COMPARISON TO OUR CURRENT HIT COMPOUNDS. LONG-TERM SUCCESS OF THIS PROJECT IS PREDICATED ON SYNERGISTIC EXPERTISE IN COMPUTATIONAL CHEMISTRY, PLATELET BIOCHEMISTRY, CRYSTALLOGRAPHY, AND DRUG DISCOVERY. SUCCESSFUL COMPLETION OF THE RESEARCH PROPOSED IN THIS GRANT HAS FUNDAMENTAL RELEVANCE TO COMMERCIAL DEVELOPMENT OF A NEW CLASS OF PLATELET ENHANCING COMPOUNDS FUNCTIONING INDEPENDENTLY OF THE KNOWN THROMBOPOIETIN (TPO)/C-MPL RECEPTOR AXIS. COMPOUND DEVELOPMENT AND TARGET VALIDATION PROVIDE A HIGHLY INNOVATIVE STRATEGY THAT WOULD THEORETICALLY BYPASS TOXICITIES ASSOCIATED WITH DIRECT TPO/C-MPL AGONISTS CURRENTLY IN CLINICAL USE (SUCH AS PLATELET ACTIVATION, THROMBOEMBOLIC COMPLICATIONS, AND BONE MARROW FIBROSIS), WHILE GENERATING FIRST-IN-CLASS REDOX INHIBITORS FOR FURTHER PRE-CLINICAL DEVELOPMENT. PHS 398/2590 (REV. 06/09) PAGE CONTINUATION FORMAT PAGE

2068166.00

0.00

0.00

2020-05-22

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Department of Health and Human Services

DETECTION OF FETAL PLATELETS IN MATERNAL BLOOD USING PLATELET RNA BIOMARKERS.

272302.00

0.00

0.00

2020-05-27

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Small Business Administration

ECONOMIC INJURY DISASTER GRANT

2000.00

0.00

0.00

2020-05-21

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Small Business Administration

TO PROVIDE LOANS TO RESTORE AS NEARLY AS POSSIBLE THE VICTIMS OF ECONOMIC INJURY TYPE DISASTERS TO PRE-DISASTER CONDITIONS

0.00

15100.00

15100.00