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MIRA: Atropisomerism as an inspiration for drug discovery and new chemistry

Award Number: R35GM124637
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2017
PERIOD OF PERFORMANCE END DATE: 07/30/2027

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MIRA: Atropisomerism as an inspiration for drug discovery and new chemistry - Project Summary and Abstract Obtaining selective small molecule inhibitors is a common bottleneck in drug discovery. The challenge of selectivity is exemplified by kinase inhibitors (KIs), as high active site conservation across the kinome has hindered the development of highly selective KIs. While there are 50+ FDA approved KIs, the majority inhibit many kinases, leading to adverse events in patients and limiting their use as tool compounds. Recently, chemists have implemented ‘selectivity filters’ that engage non-conserved features of a target to obtain selectivity, however, the generality of these approaches is limited, as they rely on rare occurrences. Over the past 5 years our group has been evaluating atropisomerism as a potentially general ‘selectivity filter’. Atropisomerism is a form of chirality that arises from hindered rotation about a bond where the rotational conformers are enantiomers. Depending on the degree of hindrance to bond rotation, atropisomers can exist as stable or unstable enantiomers. Many drugs exist as unstable atropisomers yet bind their biological targets in an atropisomer- specific manner. We have shown that analogs of promiscuous compounds that are ‘locked’ into a single atropisomeric conformation possess improved target selectivity and have leveraged this to obtain highly selective inhibitors of several kinases. To understand the origin of this selectivity, we analyzed over 100 kinase/small molecule co-crystal structures and observed that the bulk of dihedral conformational space about the axis was sampled by different kinases, and that a major driver of selectivity in our previous work was the preorganization of the axis into a narrow ‘target-preferred’ conformational range. This led us to hypothesize that target selectivity can be rapidly programmed into promiscuous scaffolds via preorganization of a prospective atropisomeric axis into a specific target’s preferred dihedral conformations. We are evaluating this in the context of diverse pharmaceutically privileged scaffolds, both dependent and independent of stable atropisomerism. A second long- term goal of our research program is the development of new broadly applicable atroposelective methodologies that allow for direct access to diverse classes of pharmaceutically relevant atropisomers. Over the past 5 years our group has developed atroposelective variants of nucleophilic aromatic substitution, electrophilic aromatic substitution and vicarious nucleophilic substitution, allowing for enantioselective access to diverse atropisomeric scaffolds including biaryls, heterobiaryls, diarylethers, and diarylamines. Moving forward we plan to continue this work and extend these reactivities directly to pharmaceutical scaffolds such as those seen in AMG-510 and Bosutinib. We will also extend our atroposelective toolbox to include new reactivities such as atroposelective cyclization and radical additions.


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 = $376,211 )
2025	2025	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	004	10	8/19/2025	NON-COMPETING CONTINUATION	$395,387
2025	2024	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	8	11/13/2024	NON-COMPETING CONTINUATION	$0
2025	2024	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	001	8	5/2/2025	NON-COMPETING CONTINUATION	-$206,670
2025	2024	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	003	8	6/11/2025	NON-COMPETING CONTINUATION	$0
2025	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	002	9	5/2/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$187,494
														Subtotal = $376,211

Issue Date FY: 2024 ( Subtotal = $374,962 )
2024	2024	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	8	7/16/2024	NON-COMPETING CONTINUATION	$374,962
														Subtotal = $374,962

Issue Date FY: 2023 ( Subtotal = $374,962 )
2023	2023	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	002	7	7/14/2023	NON-COMPETING CONTINUATION	$374,962
2023	2022	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	001	6	1/18/2023	COMPETING CONTINUATION	$55,768
2023	2021	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	5	1/18/2023	NON-COMPETING CONTINUATION	-$55,768
														Subtotal = $374,962

Issue Date FY: 2022 ( Subtotal = $374,962 )
2022	2022	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	6	6/17/2022	COMPETING CONTINUATION	$374,962
														Subtotal = $374,962

Issue Date FY: 2021 ( Subtotal = $376,250 )
2021	2021	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	5	7/19/2021	NON-COMPETING CONTINUATION	$376,250
														Subtotal = $376,250

Issue Date FY: 2020 ( Subtotal = $376,250 )
2020	2020	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	7/6/2020	NON-COMPETING CONTINUATION	$376,250
														Subtotal = $376,250

Issue Date FY: 2019 ( Subtotal = $376,250 )
2019	2019	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	3	7/24/2019	NON-COMPETING CONTINUATION	$376,250
														Subtotal = $376,250

Issue Date FY: 2018 ( Subtotal = $376,250 )
2018	2018	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	2	7/17/2018	NON-COMPETING CONTINUATION	$376,250
														Subtotal = $376,250

Issue Date FY: 2017 ( Subtotal = $376,250 )
2017	2017	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	7/24/2017	NEW	$376,250
														Subtotal = $376,250

Grand Total All Awards = $3,382,347

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MIRA: Atropisomerism as an inspiration for drug discovery and new chemistry

Award Number: R35GM124637

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2017

PERIOD OF PERFORMANCE END DATE: 07/30/2027

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