In this SBIR Phase I project, IllExcor Therapeutics proposes the development and evaluation of novel prodrug therapeutics as a yet untapped approach to treat sickle cell disease (SCD), a hereditary malady involving a single point hemoglobin (Hb) mutation that leads to severe adverse physiological complications culminating in painful vaso-occlusive crises, chronic endothelial damage, and progressive end-organ injury and dysfunction, ultimately leading to premature death. The small molecules proposed for therapeutic development are novel, more potent derivatives of the natural product 5-(Hydroxymethyl)furfural (5-HMF), a highly effective antisickling agent that targets the root cause of SCD by allosterically increasing Hb oxygen (O2) affinity. Notably, this compound has demonstrated potent antisickling activity with minimal toxicity in Phase I clinical trials (healthy adults and SCD patients). Additional compounds acting through the same mechanism include vanillin (and derivatives) and GBT440 (Voxelotor, currently in Phase III clinical trials). However, the biological activity of 5-HMF, its derivatives, and all antisickling compounds acting through this mechanism, centers around an aldehyde moiety that forms a Schiff-base with the N-termini of Hb ?-subunits. And while this essential aldehyde is key for bioactivity, it also undergoes rapid in vivo metabolism in most cases, and consequently, is responsible for limiting the plasma half- life and bioavailability of many promising drug candidates. Therefore, the goal of this Phase I proposal is to establish the feasibility and therapeutic potential of the most potent of our novel, metabolically labile thiazolidine ethyl ester prodrug derivatives of 5-HMF. This approach has already demonstrated the potential for more durable in vivo pharmacokinetics in our preliminary studies. The results of the proposed investigation are anticipated to help obtain critical preliminary data to support larger IND-enabling studies in Phase II. To achieve the SBIR Phase I goals, two Specific Aims are proposed. Specific Aim 1: Scale-up chemical synthesis for 3 prodrug derivatives, and a control (i.e., MSDD1, underivatized, native 5-HMF thiazolidine ethyl ester prodrug); and Specific Aim 2: Evaluate the in vivo PK/PD properties of the prodrugs in wild-type mice, and, subsequently, the most promising prodrug candidate in the Townes mouse model of SCD. While the goal of this Phase I proposal is to identify a lead SCD candidate possessing in vivo properties and efficacy to support a Phase II proposal, we anticipate that a more complete understanding of the untapped potential of prodrug derivatization may have a profound impact on the future development of allosteric Hb modifiers for a wide variety of conditions.
Public Health Relevance Statement: Sickle cell disease (SCD) is a genetic disorder that affects approximately 100,000 Americans, and millions more worldwide, with an estimated cost to the US healthcare system of over $1B annually. Until recently there had been no new therapeutics developed for SCD treatment in more than 20 years, leaving those suffering from this disease with limited clinical options. We propose the development of a novel SCD treatment using prodrugs and derivatives of 5-HMF, a natural product found in many sugar containing foods (and shown to be well tolerated in high doses in humans), to enhance the oxygen binding affinity of hemoglobin in such a way that red blood cells no longer sickle, thereby providing a new treatment option for mitigating the adverse health effects of the disease to significantly improve quality of life and longevity.
Project Terms: Acute; Adult; Adult Respiratory Distress Syndrome; Affect; Affinity; Aldehydes; Altitude; American; Animal Testing; Animals; Antisickling Agents; Binding; Bioavailable; Biological; Biological Availability; Biotechnology; Blood; Blood specimen; Cell Survival; Cessation of life; Characteristics; chemical synthesis; Chemicals; Chronic; Clinical; Complete Blood Count; Control Groups; cost estimate; Data; Development; Disease; dosage; Dose; drug candidate; Drug Kinetics; efficacy study; Endothelium; Erythrocytes; Esters; Evaluation; Event; FDA approved; Food; Functional disorder; Future; Gases; Genetic Diseases; Glutamine; Goals; Half-Life; Harvest; Health; Healthcare Systems; Hemoglobin; Hemolysis; histological studies; Hour; Human; Hypoxia; Immersion; improved; in vivo; Individual; Inherited; Investigation; Lead; Licensing; liquid chromatography mass spectrometry; Long-Term Effects; Longevity; Masks; Measurement; Measures; member; Metabolic; Metabolism; Modeling; Modification; mouse model; Mus; Mutation; Natural Products; next generation; novel; novel therapeutics; Oral; Organ; Organ failure; organ injury; Outcome; Oxygen; Pain; paraform; Pathologic; Patients; Pharmaceutical Preparations; pharmacokinetics and pharmacodynamics; Pharmacology; Pharmacotherapy; Phase; phase 2 study; Phase I Clinical Trials; Phase III Clinical Trials; Physiological; Plant Roots; Plasma; polymerization; premature; prevent; Prodrugs; Property; Quality of life; Research; scale up; Schiff Bases; Series; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; sickling; Small Business Innovation Research Grant; small molecule; sugar; targeted agent; Testing; Therapeutic; therapeutic development; Time; Tissues; Toxic effect; Treatment Cost; Universities; Validation; vanillin; vaso-occlusive crisis; Virginia; Wild Type Mouse
