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Optimization and Modes of Action of NEU-4438, a New Anti-trypanosome Lead Drug

Award Number: R01AI124046
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/19/2016
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Optimization and Modes of Action of NEU-4438, a New Anti-trypanosome Lead Drug - ABSTRACT New drugs with different modes of action than SCYX-7158, the current clinical candidate, are needed for chemotherapy of human African trypanosomiasis (HAT) caused by T. brucei spp. Starting with the FDA- approved drug lapatinib (EC50 = 1600 nM; selectivity index (SI) = 4 (compared to human HepG2 cells), we have synthesized over 540 analogs in a medicinal chemistry campaign focused on optimizing SI, toxicity profile, metabolism, physicochemical properties, aqueous solubility (Aq. Sol.) and CNS penetrance. Our new lead NEU4438 is orally bioavailable and extends the life of trypanosome-infected mice 2.4 (P = 0.008; Kaplan- Meir analysis), accompanied by a 109-fold reduction in parasitemia. A quinolinimine, NEU-4438 has excellent potency (GI50: 0.013 μM), selectivity (SI: >2000), physicochemical properties (aq. sol.: 880 μM; LogD7.4: 0.9; cLogP: 2.52) and in vitro ADME (human PPB%: 15; HLM Clint: 21.8 µl/min/mg protein; RH Clint: 13.1 µ//min/106 cells). Six NEU4438-related advanced hits are available for evaluation as possible leads, should NEU4438 fail to cure HAT in murine models of the disease. We will further our work by optimizing the quinolinimine scaffold using singleton and parallel medicinal chemistry approaches after constructing a virtual library, shaped by drug-like expectations in silico. Compounds will be synthesized and screened through a funnel established to select those with the best selectivity index, solubility, and physicochemical properties. Advanced hits will be evaluated in mice for safe safety, tissue exposure, and brain penetrance, after which those with the best features will be tested for efficacy in mice models of HAT to select lead drugs (exemplified by NEU4438), that may be progressed into preclinical candidates. Towards identification of the targets of the drug lead, NEU4438- binding proteins will be identified using photoaffinity probes. Concurrently, molecular modes of action will be studied by NEU4438 perturbation of the trypanosome proteome, followed by tests of hypotheses formulated from the proteomics data. In order to identify physiological targets, the phenotypes observed after knockdown of genes encoding NEU4438-binding proteins will be expected to “phenocopy” the effect of adding NEU4438 to T. brucei. Our achievements put us on track to deliver two new preclinical candidates, and to identify their physiological targets as well as modes of action in the next funding period.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $666,604 )
2025	2025	KENNESAW STATE UNIVERSITY	1000 CHASTAIN RD NW	KENNESAW	GA	30144	COBB	USA	Allergy and Infectious Diseases Research	000	9	5/13/2025	NON-COMPETING CONTINUATION	$666,604
														Subtotal = $666,604

Issue Date FY: 2024 ( Subtotal = $673,815 )
2024	2024	KENNESAW STATE UNIVERSITY	1000 CHASTAIN RD NW	KENNESAW	GA	30144	COBB	USA	Allergy and Infectious Diseases Research	000	8	3/22/2024	NON-COMPETING CONTINUATION	$673,815
														Subtotal = $673,815

Issue Date FY: 2023 ( Subtotal = $675,005 )
2023	2023	KENNESAW STATE UNIVERSITY	1000 CHASTAIN RD	KENNESAW	GA	30144	COBB	USA	Allergy and Infectious Diseases Research	001	7	2/28/2023	NON-COMPETING CONTINUATION	$675,005
2023	2022	KENNESAW STATE UNIVERSITY	1000 CHASTAIN RD	KENNESAW	GA	30144	COBB	USA	Allergy and Infectious Diseases Research	000	6	10/13/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $675,005

Issue Date FY: 2022 ( Subtotal = $681,374 )
2022	2022	KENNESAW STATE UNIVERSITY	1000 CHASTAIN RD	KENNESAW	GA	30144	COBB	USA	Allergy and Infectious Diseases Research	001	6	3/17/2022	NON-COMPETING CONTINUATION	$681,374
2022	2019	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	11/10/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $681,374

Issue Date FY: 2021 ( Subtotal = $688,344 )
2021	2021	KENNESAW STATE UNIVERSITY	1000 CHASTAIN RD NW	KENNESAW	GA	30144	COBB	USA	Allergy and Infectious Diseases Research	001	5	3/31/2021	COMPETING CONTINUATION	$688,344
2021	2019	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	3/23/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $688,344

Issue Date FY: 2019 ( Subtotal = $690,774 )
2019	2019	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	7/1/2019	NON-COMPETING CONTINUATION	$690,774
														Subtotal = $690,774

Issue Date FY: 2018 ( Subtotal = $662,424 )
2018	2018	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	7/26/2018	NON-COMPETING CONTINUATION	$662,424
														Subtotal = $662,424

Issue Date FY: 2017 ( Subtotal = $616,674 )
2017	2017	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	6/16/2017	NON-COMPETING CONTINUATION	$616,674
														Subtotal = $616,674

Issue Date FY: 2016 ( Subtotal = $640,299 )
2016	2016	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	8/19/2016	NEW	$640,299
														Subtotal = $640,299

Grand Total All Awards = $5,995,313

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Optimization and Modes of Action of NEU-4438, a New Anti-trypanosome Lead Drug

Award Number: R01AI124046

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/19/2016

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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