Chiral synthesis of LSD1 inhibitor GSK2879552 enabled by directed evolution of an imine reductase

Schöber, Markus; MacDermaid, Chris; Ollis, Anne A.; Chang, Sandy; Khan, Diluar; Hosford, Joseph; Latham, Jonathan; Ihnken, Leigh Anne F.; Brown, Murray J. B.; Fuerst, Douglas E.; Sanganee, Mahesh J.; Roiban, Gheorghe‐Doru

doi:10.1038/s41929-019-0341-4

Cited by 156 publications

(184 citation statements)

References 21 publications

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“…The approach described herein would be bolstered by an improved active site model based on crystal structures with complementary molecular dynamics simulations, to account for domain movements during catalysis (2,27), and the use of this method to perform semirational engineering would most likely expedite the development of new IRED-catalyzed processes compared to a very broad directed evolution approach such as that described by Schober et al (29). Where the goal is to improve an enzyme's stability under process parameters, it can be necessary to target residues away from the active site, and tools to predict the results of these changes are still in their infancy.…”

Section: Discussionmentioning

confidence: 99%

Characterization of imine reductases in reductive amination for the exploration of structure-activity relationships

et al. 2020

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Imine reductases (IREDs) have shown great potential as catalysts for the asymmetric synthesis of industrially relevant chiral amines, but a limited understanding of sequence activity relationships makes rational engineering challenging. Here, we describe the characterization of 80 putative and 15 previously described IREDs across 10 different transformations and confirm that reductive amination catalysis is not limited to any particular subgroup or sequence motif. Furthermore, we have identified another dehydrogenase subgroup with chemoselectivity for imine reduction. Enantioselectivities were determined for the reduction of the model substrate 2-phenylpiperideine, and the effect of changing the reaction conditions was also studied for the reductive aminations of 1-indanone, acetophenone, and 4-methoxyphenylacetone. We have performed sequence-structure analysis to help explain clusters in activity across a phylogenetic tree and to inform rational engineering, which, in one case, has conferred a change in chemoselectivity that had not been previously observed.

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Section: Discussionmentioning

confidence: 99%

Characterization of imine reductases in reductive amination for the exploration of structure-activity relationships

et al. 2020

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“…[57] Workers at GSK reported the application of GSK_IR46 from Saccharothrix espanaensis (Uniprot ID: K0K1B1) to the synthesis of the lysine-specific demethylase-1 (LSD1) inhibitor GSK2879552 precursor 62l from aldehyde 62 and racemic trans-2phenylcyclopropylamine sulfate salt l (Scheme 15). [58] Scheme 15. Synthesis of LSD-1inhibitor GSK2879552 precursor 62l by reductive amination using mutant 'M3' of IRED GSK_IR46 acquired by directed evolution.…”

Section: Imine Reductases (Ireds) Active Toward Carbonyl-containing Smentioning

confidence: 99%

NAD(P)H‐Dependent Enzymes for Reductive Amination: Active Site Description and Carbonyl‐Containing Compound Spectrum

et al. 2020

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The biocatalytic asymmetric synthesis of amines from carbonyl compounds and amine precursors presents an important advance in sustainable synthetic chemistry. Oxidoreductases (ORs) that catalyze the NAD(P)Hdependent reductive amination of carbonyl compounds directly to amines using amine donors present advantages complementary to those of amine transaminases (ATAs) with respect to selectivity, stability and substrate scope. Indeed some ORs accept alkyl and aryl amines as reaction partners enabling access to chiral secondary amine products that are not directly accessible using ATAs. Moreover, superior atom economy can usually be achieved as no sacrificial amines are required as with ATAs. In recent years a number of ORs that apparently catalyze both imine formation and imine reduction in the reductive amination of carbonyls has been identified using structure informed protein engineering, sequence analysis from natural biodiversity and increasingly a mixture of both. In this review we summarize the development of such enzymes from the engineering of amino acid dehydrogenases (AADHs) and opine dehydrogenases (OpDHs) to become amine dehydrogenases (AmDHs), which are active toward ketones devoid of any requisite carboxylate and/or amine functions, through to the discovery of native AmDHs and reductive aminases (RedAms), and the engineering of all of these scaffolds for improved or altered activity. Structural and mechanistic studies have revealed similarities, but also differences in the determinants of substrate binding and mechanism in the enzymes. The survey reveals that a complementary approach to enzyme discovery that utilizes both natural genetic resources and engineering can be combined to deliver biocatalysts that have significant potential for the industrial synthesis of chiral amines.

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“…Given the potential of RedAms for large-scale processes, 32 we used 4-phenyl cyclohexanone (15) and ammonia (f) as model reaction components to test higher substrate loadings ( Fig. S8 and S9 in the ESI †).…”

Section: Synthetic Potential For Large-scale Processesmentioning

confidence: 99%

Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases

et al. 2020

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Chiral synthesis of LSD1 inhibitor GSK2879552 enabled by directed evolution of an imine reductase

Cited by 156 publications

References 21 publications

Characterization of imine reductases in reductive amination for the exploration of structure-activity relationships

Characterization of imine reductases in reductive amination for the exploration of structure-activity relationships

NAD(P)H‐Dependent Enzymes for Reductive Amination: Active Site Description and Carbonyl‐Containing Compound Spectrum

Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases

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