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High-Affinity Alkynyl Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT) Rocco L

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High-Affinity Alkynyl Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT) Rocco L Subscriber access provided by JUBILANT ORGANOSYS LTD Article High-Affinity Alkynyl Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT) Rocco L. Policarpo, Ludovic Decultot, Elizabeth May, Petr Kuzmic, Samuel Carlson, Danny Huang, Vincent Chu, Brandon A. Wright, Saravanakumar Dhakshinamoorthy, Aimo Kannt, Shilpa Rani, Sreekanth Dittakavi, Joseph D. Panarese, Rachelle Gaudet, and Matthew D. Shair J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.9b01238 • Publication Date (Web): 07 Oct 2019 Downloaded from pubs.acs.org on October 8, 2019 Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. 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ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts. is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties. Page 1 of 188 Journal of Medicinal Chemistry 1 High-Affinity Alkynyl Bisubstrate Inhibitors of Nicotinamide 2 3 N-Methyltransferase (NNMT) 4 5 Rocco L. Policarpoa, Ludovic Decultota, Elizabeth Mayb, Petr Kuzmičc, Samuel Carlsonb, 6 7 Danny Huanga, Vincent Chua,1, Brandon A. Wrighta,2, Saravanakumar Dhakshinamoorthyd, 8 Aimo Kannte, Shilpa Ranid, Sreekanth Dittakavid, Joseph D. Panaresea,3, Rachelle Gaudetb, 9 10 Matthew D. Shaira* 11 12 13 aDepartment of Chemistry and Chemical Biology and bDepartment of Molecular and Cel- 14 15 lular Biology, Harvard University, Cambridge MA 02138, USA 16 cBioKin Ltd., Watertown MA 02472, USA 17 18 dJubilant Biosys Ltd., Yeshwantpur Bangalore - 560 022, Karnataka, India 19 eSanofi Research and Development, Industriepark Hoechst, H823, D-65926, Frankfurt am 20 21 Main, Germany 22 23 24 25 ABSTRACT 26 Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that methylates nic- 27 28 29 otinamide (NAM) using cofactor S-adenosylmethionine (SAM). NNMT overexpression 30 31 32 has been linked to diabetes, obesity, and various cancers. In this work, structure-based ra- 33 34 tional design led to the development of potent and selective alkynyl bisubstrate inhibitors 35 36 37 of NNMT. The reported nicotinamide-SAM conjugate (named NS1) features an alkyne as 38 39 40 a key design element that closely mimics the linear, 180° transition state geometry found 41 42 43 in the NNMT-catalyzed SAM → NAM methyl transfer reaction. NS1 was synthesized in 44 45 14 steps and found to be a high-affinity, subnanomolar NNMT inhibitor. An X-ray co- 46 47 48 crystal structure and SAR study revealed the ability of an alkynyl linker to span the methyl 49 50 51 transfer tunnel of NNMT with ideal shape complementarity. The compounds reported in 52 53 this work represent the most potent and selective NNMT inhibitors reported to date. The 54 55 1 56 57 58 59 60 ACS Paragon Plus Environment Journal of Medicinal Chemistry Page 2 of 188 1 rational design principle described herein could potentially be extended to other methyl- 2 3 transferase enzymes. 4 5 6 7 8 9 INTRODUCTION 10 11 12 Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme responsible for the 13 14 methylation of nicotinamide (NAM) using the cofactor S-adenosylmethionine (SAM), re- 15 16 17 sulting in the production of 1-methylnicotinamide (MNAM) and S-adenosylhomocysteine 18 19 1-2 20 (SAH). While initially established as a vitamin B3 clearance enzyme, recent work has 21 22 shown NNMT to be an important regulator of several intracellular pathways in fat, liver, 23 24 25 and cancer cells.2 NNMT can regulate methyl donor metabolism by direct interaction with 26 27 3 28 proteins of the methionine cycle and can regulate hepatic nutrient metabolism through 29 30 Sirt1 stabilization4. By decreasing cellular SAM levels, NNMT can modulate the epige- 31 32 33 netic landscape of cancer cells5 and embryonic-stem cells6. 34 35 36 Accordingly, NNMT has emerged as a disease-relevant enzyme and a possible point of 37 38 39 therapeutic intervention. Abnormal NNMT expression is implicated in several diseases, 40 41 including diabetes7-8, obesity7, 9, and a variety of cancers2, 5, 10. Increased NNMT protein expres- 42 43 44 sion was observed in adipose and liver tissue of obese and diabetic mice7, while increased 45 46 47 NNMT mRNA expression was observed in humans11. NNMT is overexpressed in glioblas- 48 49 50 toma, leading to cellular SAM depletion, DNA hypomethylation, and accelerated tumor 51 52 53 54 55 2 56 57 58 59 60 ACS Paragon Plus Environment Page 3 of 188 Journal of Medicinal Chemistry 12 1 growth. Recently, NNMT was shown to be a master metabolic regulator of cancer-asso- 2 3 ciated fibroblasts, with NNMT expression supporting ovarian cancer migration, prolifera- 4 5 6 tion, and metastasis.13 The successful development of potent and selective NNMT inhibitors 7 8 9 would aid efforts to elucidate the role of NNMT in disease, potentially enabling new strat- 10 11 egies to treat a variety of metabolic disorders, cancers, and other pathologies. 12 13 14 Several NNMT inhibitors have been reported, including methylated quinolines14, nicotin- 15 16 17 amide analogues15-16, covalent inhibitors17-18, and amino-adenosine derived bisubstrate inhibi- 18 19 19-21 20 tors . Bisubstrate inhibitors are compounds that bind both the substrate and cofactor bind- 21 22 ing pockets within an enzyme active site. The design of bisubstrate inhibitors relates 23 24 25 closely to two well-established ligand design strategies: transition-state mimicry and frag- 26 27 22 28 ment-based design. Importantly, if two weak inhibitors that bind a protein at distinct sites 29 30 are linked in an optimal manner, the resulting bisubstrate inhibitors can obtain several or- 31 32 33 ders of magnitude increase in binding affinity.23-24 As a result, linker identity is crucial to 34 35 36 properly position the key interacting groups of the two component molecules and minimize 37 38 39 unfavorable interactions between the linker and the protein. 40 41 In this work, we used a combination of structure-based design and molecular docking to 42 43 44 develop high-affinity alkynyl bisubstrate inhibitors of NNMT. To begin, we examined the 45 46 47 substrate-bound NNMT co-crystal structure (PDB ID 3ROD) and noted that the NAM ni- 48 49 50 trogen and SAH sulfur atoms are positioned ~ 4 Å apart and reside in a small tunnel that 51 52 25 facilitates the SN2-type methyl transfer reaction (Figure 1a,b). We envisioned an alkyne as 53 54 55 3 56 57 58 59 60 ACS Paragon Plus Environment Journal of Medicinal Chemistry Page 4 of 188 1 the optimal linker between a NAM-like and a SAM-like fragment, as an alkyne linker 2 3 resembles the linear, 180° transition state geometry found in the SAM → NAM methyl 4 5 6 transfer reaction (Figure 1c,d). 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 Figure 1. Overview of the alkynyl bisubstrate strategy. (a) Binding pose of ligands SAH 40 41 42 and NAM (teal) rendered from previously published co-crystal structure (PDB ID 3ROD). 43 44 45 (b) Graphical representation of the SAM → NAM methyl transfer reaction catalyzed by 46 47 48 NNMT. (c) Graphical representation of alkynyl bisubstrate inhibitor NS1 posed to mimic 49 50 the binding geometry of SAM/NAM. (d) Molecular docking output pose of alkynyl bisub- 51 52 53 strate inhibitor NS1 (black) overlaid with SAH and NAM from structure 3ROD (teal). 54 55 4 56 57 58 59 60 ACS Paragon Plus Environment Page 5 of 188 Journal of Medicinal Chemistry 1 Thus, we rationally designed alkynyl nicotinamide-SAM conjugate 1 (named NS1, 10). 2 3 Molecular docking with Glide26 predicted NS1 to be a better binder than SAM by > 3 4 5 6 kcal/mol (see Supporting Information Part 1). The docked pose of NS1 (Figure 1d) over- 7 8 9 lays well with NAM and SAH in the previously published substrate-bound crystal struc- 10 11 ture; the alkyne linker fits well into the methyl transfer tunnel. With molecular docking 12 13 14 suggesting NS1 as a potential NNMT inhibitor, we aimed to synthesize and test NS1 in an 15 16 17 NNMT inhibition assay. 18 19 20 6’-alkynyl nucleosides were first proposed and synthesized in 1990 as mixtures of al- 21 22 kynyl and amino acid diastereomers.27 Unfortunately, the designed alkynyl nucleosides 23 24 25 were poor inhibitors when tested against catechol O-methyltransferase (COMT).28 In this 26 27 28 work, we demonstrate that the alkynyl bisubstrate strategy toward SAM-dependent me- 29 30 thyltransferase inhibition is a valuable approach.
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