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Novel inhibitor for oncogenic RAS for lung cancer

Award Number: R01CA254197
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Novel inhibitor for oncogenic RAS for lung cancer - Project Summary/Abstract: Aberrant activation of RAS signaling is a major driver of lung cancer resulting from gain-in-function mutations in RAS genes often caused by tobacco-derived carcinogens. Constitutive activation of RAS, a GTPase, stimulates a cascade of downstream kinases to activate genes encoding for proteins essential for multiple aspects of tumorigenesis, including tumor cell proliferation, survival, and metastasis. Because KRAS is mutated during early stages of lung cancer and a major driver of tumor promotion and progression, a direct-acting, reversible, small molecule inhibitor of activated RAS holds great potential for lung cancer chemoprevention or the treatment of individuals with early stage disease. Unfortunately, previous attempts to develop RAS inhibitors were unsuccessful, in part, because of the scarcity of sites on the protein amenable to small-molecule binding. However, ongoing clinical trials of two covalent inhibitors of the relatively rare KRAS G12C mutation have validated this approach that can be expanded to inhibitors effective for a much broader spectrum of RAS mutations prevalent in lung cancer patients and other RAS-driven malignancies. A long-running medicinal chemistry program undertaking the synthesis of a focused library of indenes and screening in a cell-based assay for RAS selectivity resulted in the discovery of a novel class of RAS inhibitors. MCI-062 emerged as a lead compound following extensive chemical optimization and iterative target-directed screening. In vitro treatment of lung cancer cells harboring mutant RAS with MCI-062 inhibited growth with IC50 values as low as 2 nM, while human normal airway epithelial cells or tumor cells with low levels of activated RAS were essentially insensitive. MCI-062 was effective regardless of the RAS isozyme or mutational codon and appreciably more potent than covalent mutant-specific inhibitors of KRAS in clinical trials. Multiple lines of evidence indicate that MCI-062 inhibits tumor cell growth by directly interacting with RAS to inhibit GTP binding, blocking RAS-effector interaction, suppressing RAF/MAPK and PI3K/AKT signaling, resulting in selective apoptosis of RAS mutant tumor cells. As proof-of-concept, MCI-062 and a prototype prodrug, MCI-316, inhibited tumor growth in vivo, although further chemical optimization is needed to develop an oral formulation suitable for preclinical development. A new prodrug, MCI-1004 recently emerged from ongoing synthetic efforts with attractive drug-like properties that merit in vivo testing. We propose aims to: 1) gain further insight into how MCI- 062 selectively inhibits the growth of lung cancer cells with activated RAS; 2) synthesize new analogs and prodrugs to improve antitumor activity by oral delivery and benchmark them against MCI-1004, and 3) evaluate antineoplastic activity of MCI-1004 and a second prodrug lead in mouse models of lung cancer chemoprevention and treatment that are relevant to the clinic. The aims are structured to be conducted in parallel and designed to be translational with the goals of optimizing and selecting a drug development candidate for IND-enabling safety assessment and to gain a mechanistic rationale for biomarkers that will aid in selecting patient cohorts for future clinical trials.


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 = $381,222 )
2025	2025	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Cancer Treatment Research	000	6	5/27/2025	NON-COMPETING CONTINUATION	$381,222
														Subtotal = $381,222

Issue Date FY: 2024 ( Subtotal = $360,373 )
2024	2024	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Cancer Treatment Research	000	5	6/6/2024	NON-COMPETING CONTINUATION	$360,373
														Subtotal = $360,373

Issue Date FY: 2023 ( Subtotal = $395,336 )
2023	2023	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Cancer Treatment Research	000	4	6/19/2023	NON-COMPETING CONTINUATION	$395,336
														Subtotal = $395,336

Issue Date FY: 2022 ( Subtotal = $390,583 )
2022	2022	AUBURN UNIVERSITY	107 SAMFORD HALL	AUBURN	AL	36849	LEE	USA	Cancer Treatment Research	000	3	7/13/2022	NON-COMPETING CONTINUATION	$390,583
														Subtotal = $390,583

Issue Date FY: 2021 ( Subtotal = $394,586 )
2021	2021	AUBURN UNIVERSITY	107 SAMFORD HALL	AUBURN	AL	36849	LEE	USA	Cancer Treatment Research	002	2	9/10/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$394,586
2021	2021	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Cancer Treatment Research	000	1	12/7/2020	NEW	$394,585
2021	2021	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Cancer Treatment Research	001	1	9/9/2021	NEW	-$394,585
														Subtotal = $394,586

Grand Total All Awards = $1,922,100

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Novel inhibitor for oncogenic RAS for lung cancer

Award Number: R01CA254197

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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