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Development of Potent, Selective, Non-Myelotoxic FLT3 Inhibitors that Retain Efficacy Against Common Mechanisms of Resistance

Award Number: R01CA249282
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT Activating mutations in tyrosine kinase are common in human myeloid malignancies. Our long-term goal is to improve outcomes in patients with myeloid malignancies through basic and translational studies. FLT3 is the most commonly mutated gene in acute myeloid leukemia (AML). The objective of this grant is to build upon recent advances in medicinal chemistry that are pushing the boundaries of targeted therapeutics, to further inform kinase and disease biology, and to override evolving mechanisms of on- and off-target resistance to these agents. The central hypothesis is that basic and translational studies employing state-of-the-art molecular tools to interrogate clinically-relevant models of resistant disease will inform novel therapeutic approaches and advance our understanding of human leukemia biology. Our rationale is that pioneering work on BCR-ABL1 in chronic myeloid leukemia represents a paradigm that can successfully be applied to other myeloid malignancies. Previously, we provided compelling evidence validating activated FLT3 as a therapeutic target in human AML. This work rekindled efforts to develop potent and selective FLT3 kinase inhibitors that minimize vulnerabilities to resistance-conferring secondary kinase domain mutations in FLT3-ITD and led to the recent approval of gilteritinib. However, gilteritinib causes myelosuppression that limits its utility. Our preclinical work nominated activating RAS mutations as potential mediators of off-target resistance, and our recent translational studies of patients treated with gilteritinib have confirmed activated RAS as the dominant mechanism of acquired resistance to this drug. We propose to develop best-in-class FLT3 tyrosine kinase inhibitors (TKIs) that are impervious to on-target resistance mutations and devoid of hematologic toxicity. We further propose studies to identify and exploit vulnerabilities in NRAS-mutant FLT3-ITD-positive AML cells. Our specific aims will test the following hypotheses: (Aim 1) That potent and selective FLT3 inhibitors will have a sufficient therapeutic index to enable them to retain activity against common secondary kinase domain mutants and will be devoid of hematologic toxicity; (Aim 2) That coexistence of pathologically activated FLT3 and NRAS will create novel dependencies that can be exploited therapeutically; and (Aim 3) That structural studies and compound optimization can identify active compounds with drug-like properties. Upon conclusion of these studies, we will have a more detailed understanding of chemical scaffolds that potently and selectively target FLT3, novel understanding of AML cells that contain co-existent FLT3-ITD and NRAS mutations, insights into therapeutic vulnerabilities in this setting, and novel therapeutics. This contribution is significant since it has the potential to rapidly impact clinical investigation and therapeutic outcomes. The proposed research is innovative because it proposes application of state-of-the-art methodologies to systematically probe the molecular underpinnings of AML resistant to targeted therapeutics, and combine them with expertise in chemical structural biology. This work is potentially highly impactful as AML remains associated with a poor prognosis.


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: 2024 ( Subtotal = $620,109 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	002	4	4/16/2024	NON-COMPETING CONTINUATION	$32,638
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Treatment Research	000	4	12/8/2023	NON-COMPETING CONTINUATION	$587,471
2024	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	001	3	2/26/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $620,109

Issue Date FY: 2023 ( Subtotal = $749,303 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Treatment Research	000	3	12/9/2022	NON-COMPETING CONTINUATION	$587,469
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Treatment Research	002	3	9/21/2023	SUPPLEMENT FOR EXPANSION	$109,614
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Treatment Research	001	3	3/16/2023	NON-COMPETING CONTINUATION	$52,220
														Subtotal = $749,303

Issue Date FY: 2022 ( Subtotal = $642,786 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Treatment Research	001	2	5/20/2022	NON-COMPETING CONTINUATION	$52,473
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Treatment Research	000	2	11/23/2021	NON-COMPETING CONTINUATION	$590,313
														Subtotal = $642,786

Issue Date FY: 2021 ( Subtotal = $685,777 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Treatment Research	000	1	12/8/2020	NEW	$685,777
														Subtotal = $685,777

Grand Total All Awards = $2,697,975

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Development of Potent, Selective, Non-Myelotoxic FLT3 Inhibitors that Retain Efficacy Against Common Mechanisms of Resistance

Award Number: R01CA249282

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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