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The design, synthesis, and characterization of potent and selective MEK7 inhibitors as targeted therapies for T-cell acute lymphoblastic leukemia

Award Number: F31CA228431
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Project Summary Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy in pediatric patients and the most frequent cause of cancer-related mortality before the age of 20. Current treatment strategies act by non-specific mechanisms that are incapable of achieving and maintaining remission in the nearly 1 out of 4 pediatric patients with therapy-resistant disease. While targeted therapies are not currently available for ALL patients, they could potentially improve patient outcomes by interfering with pathological cellular and molecular activities that facilitate resistance to multi-agent chemotherapy. Increased expression of protein kinase MEK7 and consequent amplification of downstream MAP kinase signaling have been identified as two such processes facilitating chemoresistance in T-cell ALL (T-ALL), rendering MEK7 an attractive target for T-ALL directed therapies. Unfortunately, there are no small molecules known to potently and selectively inhibit this MEK isoform. Leveraging our published platform for interrogating inhibitor selectivity across the MEK kinase family, we have designed and synthesized a lead compound exhibiting potent MEK7 inhibition. The objective of my present proposal is the further development and optimization of a potent and selective small molecule MEK7 inhibitor to chemically probe aberrant signaling in this arm of the MAPK pathway in T-ALL models. Our methodology entails a multifaceted approach employing strategies from disciplines spanning computational chemistry, organic synthesis, protein biochemistry, and molecular biology. Through these complementary modalities, we seek to gain new insight into the roles of the least understood MEK isoform in the molecular pathophysiology underlying T-ALL. Of utmost clinical significance, the studies in this proposal will survey the efficacy of direct MEK7 inhibitors as targeted therapies for T-ALL.


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 = -$1,762 )
2024	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	000	4	12/28/2023	NON-COMPETING CONTINUATION	-$1,762
														Subtotal = -$1,762

Issue Date FY: 2022 ( Subtotal = $50,070 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	001	4	5/20/2022	NON-COMPETING CONTINUATION	$716
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	000	4	4/1/2022	NON-COMPETING CONTINUATION	$49,354
														Subtotal = $50,070

Issue Date FY: 2021 ( Subtotal = $49,354 )
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	001	3	2/23/2021	NON-COMPETING CONTINUATION	$49,354
2021	2020	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	000	2	11/9/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $49,354

Issue Date FY: 2020 ( Subtotal = $48,838 )
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	000	2	11/22/2019	NON-COMPETING CONTINUATION	$48,336
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	001	2	3/11/2020	NON-COMPETING CONTINUATION	$502
														Subtotal = $48,838

Issue Date FY: 2018 ( Subtotal = $47,842 )
2018	2018	NORTHWESTERN UNIVERSITY	633 CLARK ST EVANSTON	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	001	1	9/14/2018	NEW	$0
2018	2018	NORTHWESTERN UNIVERSITY	633 CLARK ST EVANSTON	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	000	1	9/14/2018	NEW	$47,842
														Subtotal = $47,842

Grand Total All Awards = $194,342

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The design, synthesis, and characterization of potent and selective MEK7 inhibitors as targeted therapies for T-cell acute lymphoblastic leukemia

Award Number: F31CA228431

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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