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1 Supporting Information Selective DYRK1A inhibitor for the treatment of Type 1 Diabetes: Discovery of 6-azaindole derivative GNF2133 Yahu A. Liu*, Qihui Jin, Yefen Zou, Qiang Ding, Shanshan Yan, Zhicheng Wang, Xueshi Hao, Bao Nguyen, Xiaoyue Zhang, Jianfeng Pan, Tingting Mo, Kate Jacobsen, Thanh Lam, Tom Y.-H. Wu, H. Michael Petrassi, Badry Bursulaya, Michael DiDonato, W. Perry Gordon, Bo Liu, Janine Baaten, Robert Hill, Vân Nguyen-Tran, Minhua Qiu, You-Qing Zhang, Anwesh Kamireddy, Sheryll Espinola, Lisa Deaton, Sukwon Ha, George Harb, Yong Jia, Jing Li, Weijun Shen, Andrew M. Schumacher, Karyn Colman, Richard Glynne, Shifeng Pan, Peter McNamara, Bryan Laffitte, Shelly Meeusen, Valentina Molteni, Jon Loren* Genomics Institute of the Novartis Research Foundation (GNF), John Jay Hopkins Drive, San Diego, California 92121, United States yliu2@gnf.org; Phone: jloren@gnf.org; Phone: S1
2 Table of Contents Part I 1 H, 13 C and 2D NMR of the compounds in Experimental Section S5-S30 Figure S1. 1 H NMR of 2 in DMSO-d 6 (500 MHz) Figure S2. 1 H NMR of 3e in DMSO-d 6 (500 MHz) Figure S3. 1 H NMR of 5e in DMSO-d 6 (500 MHz) Figure S4. 1 H NMR of 5f in DMSO-d 6 (400 MHz) Figure S5. HMQC NMR of 5f in DMSO-d 6 (400 MHz) Figure S6. COSY NMR of 5f in DMSO-d 6 (400 MHz) Figure S7. NOESY NMR of 5f in DMSO-d 6 (400 MHz) Figure S8. 1 H NMR of 5g in DMSO-d 6 (500 MHz) Figure S9. 1 H NMR of 6 in DMSO-d 6 (500 MHz) Figure S10. 1 H NMR of 7 in DMSO-d 6 (400 MHz) Figure S11. 1 H NMR of 8a in DMSO-d 6 (400 MHz) Figure S12. 1 H NMR of 8b in MeOH-d 4 (400 MHz) Figure S13. 1 H NMR of 8c in DMSO-d 6 (600 MHz) Figure S14. 1 H NMR of 8d in MeOH-d 4 (400 MHz) Figure S15. 1 H NMR of 8e in DMSO-d 6 (400 MHz) Figure S16. 1 H NMR of 8f, in MeOH-d 4 (400 MHz) Figure S17. NMR analysis of 8f in DMSO-d 6 (600 MHz) Figure S18. 1 H NMR of 8f in DMSO-d 6 (600 MHz) Figure S19. HMQC of 8f in DMSO-d 6 (600 MHz) Figure S20. COSY of 8f in DMSO-d 6 (600 MHz) Figure S21. HMBC of 8f in DMSO-d 6 (600 MHz) Figure S22. ROESY of 8f in DMSO-d 6 (600 MHz) Figure S23. NMR analysis of 8f in DMSO-d 6 (600 MHz) Figure S24. 1 H NMR of 8f in DMSO-d 6 (600 MHz) Figure S25. HMQC of 8f in DMSO-d 6 (600 MHz) Figure S26. COSY of 8f in DMSO-d 6 (600 MHz) Figure S27. HMBC of 8f in DMSO-d 6 (600 MHz) Figure S28. ROESY of 8f in DMSO-d 6 (600 MHz) Figure S29. 1 H NMR of 8g in DMSO-d 6 (400 MHz) Figure S30. 1 H NMR of 9e in DMSO-d 6 (500 MHz) Figure S31. 1 H NMR of 10e in MeOH-d 4 (400 MHz) Figure S32. 1 H NMR of 10g in DMSO-d 6 (400 MHz) Figure S33. 1 H NMR of 11a in MeOH-d 4 (400 MHz) Figure S34. 1 H NMR of 12e in DMSO-d 6 (500 MHz) Figure S35. 1 H NMR of 12g in DMSO-d 6 (500 MHz) S2 S5 S5 S6 S6 S7 S8 S9 S10 S11 S11 S12 S12 S13 S13 S14 S14 S15 S15 S16 S16 S17 S17 S18 S18 S19 S19 S20 S20 S21 S21 S22 S22 S23 S23 S24
3 Figure S36. 1 H NMR of 13a in DMSO-d 6 (500 MHz) Figure S C NMR of 13a in DMSO-d 6 (125 MHz) Figure S38. 1 H NMR of 13b in DMSO-d 6 (400 MHz) Figure S39. 1 H NMR of 13c in MeOH-d 4 (400 MHz) Figure S40. 1 H NMR of 13d in DMSO-d 6 (400 MHz) Figure S C NMR of 13d in DMSO-d 6 (125 MHz)) Figure S42. 1 H NMR of 13e in DMSO-d 6 (400 MHz) Figure S C NMR of 13e in DMSO-d 6 (125 MHz)) Figure S44. 1 H NMR of 13f in DMSO-d 6 (600 MHz) Figure S C NMR of 13f in DMSO-d 6 (125 MHz) Figure S46. 1 H NMR of 13g in DMSO-d 6 (400 MHz) Figure S C NMR of 13g in DMSO-d 6 (100 MHz) Figure S48. 1 H NMR of 13g (HCl salt) in DMSO-d 6 (400 MHz) S24 S25 S25 S26 S26 S27 S27 S28 S28 S29 S29 S30 S30 Part II Structure-activity relationship (SAR) of the core framework S31-S45 Table S1. Structure-activity relationship (SAR) of the core framework Table S2. Analytical data of the compounds listed in Table S1 S31 S33 Figure S49-S70. 1 H, 13 C and 2D NMR of the compounds in Table S1 S35-S45 Figure S49. 1 H NMR of 8h in DMSO-d 6 (600 MHz) Figure S50. 1 H NMR of 9g in DMSO-d 6 (400 MHz) Figure S51. 1 H NMR of 13h in MeOH-d 4 (500 MHz) Figure S52. 1 H NMR of 14 in CDCl 3 (400 MHz) Figure S53. 1 H NMR of 15 in MeOH-d 4 (400 MHz) Figure S54. 1 H NMR of 16 in MeOH-d 4 (400 MHz) Figure S55. 1 H NMR of 17 in CDCl 3 (400 MHz) Figure S56. 1 H NMR of 17 in DMSO-d 6 (600 MHz) Figure S C NMR of 17 in DMSO-d 6 (600 MHz) Figure S58. HMQC NMR of 17 in DMSO-d 6 (600 MHz) Figure S59. COSY NMR of 17 in DMSO-d 6 (600 MHz) Figure S60. HMBC NMR of 17 in DMSO-d 6 (600 MHz) Figure S61. ROESY NMR of 17 in DMSO-d 6 (600 MHz) Figure S62. 1 H NMR of 22 in DMSO-d 6 (400 MHz) Figure S63. 1 H NMR of 23 (TFA salt) in MeOH-d 4 (400 MHz) Figure S64. 1 H NMR of 24 in CDCl 3 (400 MHz0 Figure S65. 1 H NMR of 25 in MeOH-d 4 (400 MHz) Figure S66. 1 H NMR of 26 (TFA salt) in DMSO-d 6 (400 MHz) Figure S67. 1 H NMR of 27 in DMSO-d 6 (400 MHz) S35 S35 S36 S36 S37 S37 S38 S38 S39 S39 S40 S40 S41 S41 S42 S42 S43 S43 S44 S3
4 Figure S68. 1 H NMR of 28 in MeOH-d 4 (400 MHz) Figure S69. 1 H NMR of 29 in MeOH-d 4 (400 MHz) Figure S70. 1 H NMR of 30 in MeOH-d 4 (400 MHz) S44 S45 S45 Part III Images and dose repsonse of rat and human cell proliferation S46-S47 Figure S71. Images of rat and human primary β-cell replication Figure S72. Dose response of rat and human β-cell proliferation S46 S47 Part IV X-ray co-crystal structure of DYRK1A and GNF2133 S48-S50 Protein expression and purification S48 Crystallization and data collection S48 Structure Determination and refinement S48 Figure S73. Resolution of X-ray co-crystal structure S49 Table S3. Crystallographic data and refinement statistics S50 Part V Two-week in vivo safety study of GNF2133 S51 Part VI Kinase inhibition profiling and Ba/F3 cellular profiling of GNF2133 S52-S56 Table S4. GNF2133 in enzymatic cell free Caliper microfluidic kinase assay S52 Table S5. GNF2133 in Ba/F3 cellular kinase Profiling S56 References S57 S4
5 Part I. 1 H, 13 C and 2D NMR of the compounds in Experimental Section Figure S1. 1 H NMR of 2 in DMSO-d6 (500 MHz) Figure S2. 1 H NMR of 3e in DMSO-d6 (500 MHz) S5
6 Figure S3. 1 H NMR of 5e in DMSO-d6 (500 MHz) Figure S4. 1 H NMR of 5f in DMSO-d6 (400 MHz) S6
7 Figure S5. HMQC NMR of 5f in DMSO-d6 (400 MHz) S7
8 Figure S6. COSY NMR of 5f in DMSO-d6 (400 MHz) S8
9 Figure S7. NOESY NMR of 5f in DMSO-d6 (400 MHz) (continued on next page) S9
10 (continued from previous page) Figure S7. NOESY NMR of 5f in DMSO-d6 (400 MHz) Figure S8. 1 H NMR of 5g in DMSO-d6 (500 MHz) S10
11 Figure S9. 1 H NMR of 6 in DMSO-d6 (500 MHz) Figure S10. 1 H NMR of 7 in DMSO-d6 (400 MHz) S11
12 Figure S11. 1 H NMR of 8a in DMSO-d6 (400 MHz) Figure S12. 1 H NMR of 8b in DMSO-d6 (400 MHz) S12
13 Figure S13. 1 H NMR of 8c in DMSO-d6 (600 MHz) Figure S14. 1 H NMR of 8d in MeOH-d4 (400 MHz) S13
14 Figure S15. 1 H NMR of 8e in DMSO-d6 (400 MHz) Figure S16. 1 H NMR of 8f in MeOH-d4 (400 MHz) S14
15 Figure S17. NMR analysis of 8f in DMSO-d6 (600 MHz) Figure S18. 1 H NMR of 8f in DMSO-d6 (600 MHz) S15
16 Figure S19. HMQC of 8f in DMSO-d6 (600 MHz) Figure S20. COSY of 8f in DMSO-d6 (600 MHz) S16
17 Figure S21. HMBC of 8f in DMSO-d6 (600 MHz) Figure S22. ROESY of 8f in DMSO-d6 (600 MHz) S17
18 Figure S23. NMR analysis of 8f in DMSO-d6 (600 MHz) Figure S24. 1 H NMR of 8f in DMSO-d6 (600 MHz) S18
19 Figure S25. HMQC of 8f in DMSO-d6 (600 MHz) Figure S26. COSY of 8f in DMSO-d6 (600 MHz) S19
20 Figure S27. HMBC of 8f in DMSO-d6 (600 MHz) Figure S28. ROESY of 8f in DMSO-d6 (600 MHz) S20
21 Figure S29. 1 H NMR of 8g in DMSO-d6 (400 MHz) Figure S30. 1 H NMR of 9e in DMSO-d6 (500 MHz) S21
22 Figure S31. 1 H NMR of 10e in DMSO-d6 (400 MHz) Figure S32. 1 H NMR of 10g in DMSO-d6 (400 MHz) S22
23 Figure S33. 1 H NMR of 11a in MeOH-d4 (400 MHz) Figure S34. 1 H NMR of 12e in DMSO-d6 (500 MHz) S23
24 Figure S35. 1 H NMR of 12g in DMSO-d6 (500 MHz) Figure S36. 1 H NMR of 13a in DMSO-d6 (500 MHz) S24
25 Figure S C NMR of 13a in DMSO-d6 (125 MHz) Figure S38. 1 H NMR of 13b in DMSO-d6 (400 MHz) S25
26 Figure S39. 1 H NMR of 13c MeOH-d4 (400 MHz) Figure S40. 1 H NMR of 13d in DMSO-d6 (400 MHz) S26
27 Figure S C NMR of 13d in DMSO-d6 (125 MHz) Figure S42. 1 H NMR of 13e in DMSO-d6 (400 MHz) S27
28 Figure S C NMR of 13e in DMSO-d6 (125 MHz) Figure S44. 1 H NMR of 13f in DMSO-d6 (600 MHz) S28
29 Figure S C NMR of 13f in DMSO-d6 (125 MHz) Figure S46. 1 H NMR of 13g in DMSO-d6 (400 MHz) S29
30 Figure S C NMR of 13g in DMSO-d6 (100 MHz) Figure S48. 1 H NMR of 13g (HCl salt) in DMSO-d6 (400 MHz) S30
31 Part II. Structure-activity relationship (SAR) of the core framework Table S1. Structure-activity relationship (SAR) of the core framework compound R 1 R 2 J L M Q T X Y Z a IC 50 (µm) DYRK1A GSK3 IC 50 a (µm) 8h CH CH N CH C N CH C N CH N CH C N CH C >50 8g CH CH N CH C N CH C > CH CH N CH N C N C >50 16 CH CH N CH C N CH C >16 >50 8a CH CH N CH C N CH C > CH CH N CH C N N C CH C-Cl CH CH C N N C >50 >50 19 CH C-OMe CH CH C N N C >50 20 CH C-Cl CH N C N N C >14 >50 21 CH C-OMe CH N C N N C >50 >50 (continued on next page) S31
32 Table S1. (continued) compound R 1 R 2 J L M Q T X Y Z a IC 50 (µm) DYRK1A GSK3 IC 50 a (µm) 9g CH CH N CH C N CH C >50 22 CH CH N CH C N C=O N >50 >50 23 CH C-OH N CH C N CH C >50 24 CH C-Cl N CH C N CH C CH C-OMe N CH C N CH C >50 >50 10e CH H N CH C N CH C >50 26 CH H N C-Me C N CH C >50 27 CH H N C-Cl C N CH C >50 13h CH CH N CH C N CH C >50 28 C-Me CH N CH C N CH C 6.35 >50 29 C-Cl CH N CH C N CH C >50 >50 30 C-CN CH N CH C N CH C >50 >50 a Obtained from three or more independent experiments. S32
33 Table S2. Analytical data of the compounds listed in Table S1 compound 1 H NMR LCMS m/z 8h (600 MHz, DMSO-d 6 ) δ 5.60 (s, 2H), (2H), (2H), 7.74 (d, J = 6.1 Hz, 2H), 7.98 (d, J = 5.4 Hz, 1H), 8.27 (d, J = 5.4 Hz, 1H), 8.50 (s, 1H), 8.57 (d, J = 6.1 Hz, 2H), 8.99 (s, 1H). 304 (MH + ) 14 (400 MHz, CDCl 3 ) δ 5.43 (s, 2H), (2H), (2H), 7.90 (s, 1H), (2H), (2H), 8.82 (s, 1 H), 9.13 (s, 1 H). 305 (MH + ) 8g See Experimental Section 15 (400 MHz, MeOH-d 4 ) δ 7.44 (m, 1H), (2H), 7.69 (d, J = 5.2 Hz, 1H), (4H), 8.53 (dd, J = 5.2, 1.6 Hz, 1H), 8.77 (dd, J = 4.6, 1.6 Hz, 2H), 9.53 (d, J = 1.6 Hz, 1H). 16 (400 MHz, MeOH-d 4 ) δ 7.29 (m, 1H), (2H), (2H), (2H), 7.84 (d, J = 5.2 Hz, 1H), 8.06 (s, 1H), 8.23 (d, J = 5.2 Hz, 1H), 8.64 (d, J = 5.0 Hz, 2H), 9.00 (s, 1H). 273 (MH + ) 272 (MH + ) 8a See Experimental Section 17 (400 MHz, CDCl 3 ) δ 1.00 (d, J = 6.7 Hz, 6H), 2.44 (m, 1H), 4.35 (d, J = 7.3 Hz, 2H), (2H), 7.92 (dd, J = 5.8, 1.2 Hz, 1H), 8.43 (d, J = 5.6 Hz, 1H), (2H), 9.04 (d, J = 1.0 Hz, 1H). 253 (MH + ) (MH + ) (MH + ) (MH + ) (MH + ) 9g (400 MHz, DMSO-d 6 ) δ 1.51 (s, 9H), 7.48 (dd, J = 5.2, 1.6 Hz, 1H), 7.52 (m, 1H), (2H), (2H), 7.99 (dd, J = 5.6, 1.0 Hz, 1H), (2H), 8.53 (s, 1H), 8.96 (s, 1H), 9.79 (s, 1H). 287 (M-100+H + ) 22 (400 MHz, DMSO-d 6 ) δ 1.48 (s, 9H), (2H), 7.51 (m, 1H), (4H), 8.14 (d, J = 1.8 Hz, 1H), 8.32 (s, 1H), 8.37 (d, J = 5.3 Hz, 1H), 8.46 (d, J = 5.3 Hz, 1H), (s, 1H). 23 (400 MHz, MeOH-d 4 ) δ 0.98 (d, J = 6.6 Hz, 6H), 2.27 (m, 1H), 4.08 (d, J = 7.6 Hz, 2H), 7.14 (s, 1H), 8.16 (d, J = 6.8 Hz, 2H), 8.28 (s, 1H), 8.61 (d, J = 6.8 Hz, 2H), 8.66 (s, 1H). 304 (M-100+H + ) 268 (MH + ) (continued on next page) S33
34 Table S2. (continued) compound 1 H NMR LCMS m/z 24 (400 MHz, CDCl 3 ) δ 0.98 (d, J = 6.6 Hz, 6H), 2.26 (m, 1H), 4.08 (d, J = 7.3 Hz, 2H), (2H), 7.60 (s, 1H), 7.85 (s, 1H), 8.58 (s, 1H), (2H). 25 (400 MHz, MeOH-d 4 ) δ 0.99 (d, J = 6.6 Hz, 6H), 2.31 (m, 1H), 4.05 (s, 3H), 4.22 (d, J = 7.5 Hz, 2H), 7.53 (s, 1H), 8.30 (d, J = 6.9 Hz, 2H), (4H). 286 (MH + ) 282 (MH + ) 10e See Experimental Section 26 (400 MHz, DMSO-d 6 ) δ (4H), 3.18 (s, 3H), (2H), (2H), 5.10 (m, 1H), 7.37 (d, J = 6.8 Hz, 1H), 7.41 (s, 1H), 7.99 (br s, 2H, NH 2 ), 8.04 (d, J = 6.8 Hz, 1H), 8.18 (d, J = 6.4 Hz, 1H), 8.42 (d, J = 6.4 Hz, 1H), 9.08 (s, 1H). 27 (400 MHz, DMSO-d 6 ) δ (2H), (2H), (2H), (2H), 5.47 (m, 1H), (3H), 7.28 (br, 1H), (2H), 8.12 (d, J = 5.5 Hz, 1H), 8.57 (s, 1H). 13h (500 MHz, MeOH-d 4 ) δ 1.27 (d, J = 6.6 Hz, 6H), 4.00 (m, 1H), 7.38 (dd, J = 5.7, 1.6 Hz, 1H), 7.54 (m, 1H), (5H), 8.10 (dd, J = 5.7, 1.0 Hz, 1H), 8.24 (d, J = 5.7 Hz, 1H), 8.31 (s, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.85 (s, 1H). 28 (400 MHz, MeOH-d 4 ) δ 1.25 (d, J = 6.6 Hz, 6H), 2.42 (s, 3H), 3.99 (m, 1H), 7.08 (dd, J = 5.3, 1.0 Hz, 1H), 7.29 (s, 1H), 7.47 (m, 1H), (4H), 7.75 (s, 1H), 8.01 (s, 1H), 8.21 (d, J = 5.3 Hz, 1H), 8.67 (s, 1H). 29 (400 MHz, MeOH-d 4 ) δ 1.25 (d, J = 6.6 Hz, 6H), 3.99 (m, 1H), 7.08 (dd, J = 5.4, 1.5 Hz, 1H), 7.32 (s, 1H), 7.53 (m, 1H), (4H), 7.91 (s, 1H), 8.20 (d, J = 5.4 Hz, 1H), 8.23 (s, 1H), 8.74 (s, 1H). 30 (400 MHz, MeOH-d 4 ) δ 1.25 (d, J = 6.6 Hz, 6H), 3.99 (m, 1H), 7.24 (d, J = 5.4 Hz, 1H), 7.36 (s, 1H), 7.56 (m, 1H), (4H), 5.12 (s, 1H), 8.26 (d, J = 5.4 Hz, 1H), 8.65 (s, 1H), 9.01 (s, 1H). 309 (MH + ) 329 (MH + ) 372 (MH + ) 386 (MH + ) 406 (MH + ) 397 (MH + ) S34
35 1 H, 13 C and 2D NMR of the compounds in Table S1 Figure S49. 1 H NMR of 8h in DMSO-d6 (600 MHz) Figure S50. 1 H NMR of 9g in DMSO-d6 (400 MHz) S35
36 Figure S51. 1 H NMR of 13h in MeOH-d4 (500 MHz) Figure S52. 1 H NMR of 14 in CDCl3 (400 MHz) S36
37 Figure S53. 1 H NMR of 15 in MeOH-d4 (400 MHz) Figure S54. 1 H NMR of 16 in MeOH-d4 (400 MHz) S37
38 Figure S55. 1 H NMR of 17 in CDCl3 (400 MHz) Figure S56. 1 H NMR of 17 in DMSO-d6 (600 MHz) S38
39 Figure S C NMR of 17 in DMSO-d6 (150 MHz) Figure S58. HMQC NMR of 17 in DMSO-d6 (600 MHz) S39
40 Figure S59. COSY NMR of 17 in DMSO-d6 (600 MHz) Figure S60. HMBC NMR of 17 in DMSO-d6 (600 MHz) S40
41 Figure S61. ROESY NMR of 17 in DMSO-d6 (600 MHz) Figure S62. 1 H NMR of 22 in DMSO-d6 (400 MHz) S41
42 Figure S63. 1 H NMR of 23 (TFA salt) in MeOH-d4 (400 MHz) Figure S64. 1 H NMR of 24 in CDCl3 (400 MHz) S42
43 Figure S65. 1 H NMR of 25 in MeOH-d4 (400 MHz) Figure S66. 1 H NMR of 26 (TFA salt) in DMSO-d6 (400 MHz) S43
44 Figure S67. 1 H NMR of 27 in DMSO-d6 (400 MHz) Figure S68. 1 H NMR of 28 in MeOH-d4 (400 MHz) S44
45 Figure S69. 1 H NMR of 29 in MeOH-d4 (400 MHz) Figure S70. 1 H NMR of 30 in MeOH-d4 (400 MHz) S45
46 Figure S71. Images of rat and human primary β-cell replication. Images of dispersed rat (A) and human (B) islets treated with DMSO, 13f, 13g, or harmine, and stained with EdU (red), anti-insulin (green), or/and DAPI (blue). Images were processed in parallel and cropped. S46
47 Figure S72. Dose response of harmine, 5-IT, 13f and 13g-induced rat (A) and human (B) β-cell proliferation. The assay was performed in triplicate in each experiment. Error bars represent standard deviation. Asterisks indicate significance testing compared to DMSO-treated wells: * p < 0.05; ** < 0.01; *** p < 0.001; **** p < S47
48 Part IV. X-ray co-crystal structure of DYRK1A and GNF2133 Protein expression and purification The DYRK1A kinase domain (residues ) was expressed in E. coli (BL21(DE3) CodonPlus-RIPL, Agilent Technologies) with a cleavable N-terminal 6xHIS tag. Briefly, 14 ml of O/N culture was seeded into 1L TB media (Teknova #T7060) supplemented with the appropriate antibiotics and incubated at 37 C until an OD600 of ~0.4. The temperature was decreased to 18 until an OD600 of ~0.6 was reached at which point expression was induced with 1 mm IPTG. The induced culture was then incubated overnight at 18 C. The next morning cells were harvested by centrifugation (4000xg, 30 min, 4 ). The bacterial pellet was resuspended in lysis buffer (50 mm Tris ph 7.4, 500 mm NaCl, 10 mm Imidazole, 1 mm TCEP, 5% glycerol) supplemented with protease inhibitors (Roche). The resuspended cells were lysed by sonication and the lysate was clarified by centrifugation (36,000xg, 45 min, 4 ). The clarified lysate was applied to Ni-affinity resin previously equilibrated with 25 mm HEPES ph 7.5, 500 mm NaCl, 5 mm TCEP, 5% glycerol. Bound protein was washed with 10 CV of 25 mm HEPES ph 7.5, 500 mm NaCl, 5 mm TCEP, 5% glycerol, 10 mm imidazole and then eluted with the same wash buffer supplemented with 300 mm imidazole. The eluted protein was desalted into 25mM HEPES ph 7.5, 500 mm NaCl, 5 mm TCEP using a PD10 desalting column (GE Life Sciences). The N-terminal 6xHis tag was removed by overnight digestion with Tev protease (His-tagged) at 4 C. Uncleaved protein and Tev protease were removed by flowing the digestion mixture over Ni-affinity resin equilibrated with 25 mm HEPES ph 7.5, 500 mm NaCl, 5 mm TCEP and the flow through collected. The cleaved protein was further purified using size exclusion chromatography using a Superdex S200 (GE Life Sciences) column. Fraction containing protein were combined and concentrated to a 15 mg/ml using a 10 kda MWCO spin concentrator (Amicon). Crystallization and data collection Crystallization experiments were carried out using the sitting-drop vapor diffusion setup with 0.4 μl drops (0.2 μl protein μl reservoir solution). Prior to crystallization, the inhibitor was added to the purified DYRK1A kinase domain to a final concentration of ~0.5 mm. Crystallization experiments were carried out at both 4 and 20. Crystals for the DYRK1A-Inhibitor complex appeared in 2-3 weeks from 0.1 M Bicine ph 8.5, 15% PEG 20000, 3% Dextran sulfate at 4. Crystals were cryopreserved in reservoir solution supplemented with 20% v/v ethylene glycol and flash frozen in liquid nitrogen prior to data collection. X-ray diffraction data were collected from frozen crystals on ALS beamline Structure determination and refinement Diffraction data were processed using HKL2000 S1 and the structure was solved by molecular replacement using PHASER S2 as implemented in the CCP4 software package. S3 Structure refinement was carried out in PHENIX S4 alternated with manual fitting in Coot. S5 Restraints for the inhibitor were generated with GRADE as part of the autobuster software package. S6,S7 Due to the relatively low resolution of the structure group B-factor refinement (one per residue) and a single TLS group per chain were employed in the refinement protocol using PHENIX. S48
49 Resolution of X-ray co-crystal structure Despite the moderately low resolution of the structure (3.7 Å) the electron density in the active site and for the inhibitor is very well defined and supports the depicted binding mode. This is likely due to the low mosaicity of the crystal (0.325 ), the low Wilson b-factor (24.87 Å 2 ) and the presence of 3 copies of DYRK1A in the crystallographic asymmetric unit which allowed for the use of NCS restraints during refinement. Also, the average b-factors for the protein and across all three copies of the inhibitor are quite low (48.12 Å 2 and Å 2 respectively) relative to the overall resolution. More specifically, the average b-factor of the inhibitor bound to chain A is Å 2, the inhibitor bound to chain B is Å 2 and the inhibitor bound to chain C is Å 2. The structure and interactions depicted in Figure 5 are the inhibitor bound to chain A (the binding mode in the other chain is the same). Figure S73 depicts the 2FoFc electron density map for the inhibitor bound to chain A contoured to 1.5σ. The quality and shape of the electron density allowed for unambiguous placement of the inhibitor molecule. The observed electron density does not support a flipped binding mode. Figure S73. 2FoFc electron density map for GNF2133 bound to chain A. S49
50 Table S3. Crystallographic data and refinement statistics DYRK1A-GNF2133 PDB Code Wavelength Resolution Range (Å) ( ) Space Group P3112 Unit Cell (a, b, c, α, β, γ) , , , 90, 90, 120 Unique Reflections (2168) Multiplicity 8.4 (8.4) Completeness (%) (86.14) Mean I/sigma(I) 24.9 (1.4) Wilson B-factor Rmeas (0.00) Rpim (0.580) Reflections used for R-free 1155 (133) Rwork (36.30) Rfree (38.33) Number of non-hydrogen atoms 8203 macromolecules 8107 ligands 96 solvent 0 Protein residues 989 RMS (bonds) RMS (angles) 0.64 Ramachandran favored (%) 91.7 Ramachandran allowed (%) 7.46 Ramachandran outliers (%) 0.84 Clashscore 8.18 Average B-factor macromolecules ligands Statistics for the highest-resolution shell are shown in parentheses. S50
51 Part V. Two-week in vivo safety study of GNF2133 In order to evaluate potential off-target (non-islet) cellular proliferation, GNF2133 was administered to 8-week old male HanWistar rats by oral gavage for two weeks, at doses of 0 (vehicle control) and 100 mg/kg/day with 5 animals in each group. Samples of the liver, heart, kidney and pancreas were taken at necropsy, fixed in 10% neutral buffered formalin for 48 h, embedded in paraffin and then processed to slide. Immunohistochemical staining (Ki67) was performed using a Leica Bond RX autostainer using Leica BOND Polymer Refine Detection kit (Leica, Buffalo Grove, IL) except the deparaffinization and heat antigen retrieval steps. Slides were deparaffinized using xylene, 100% ethanol and 95% ethanol (2 changes of 3 minutes each), then rehydrated in deionized water. Slides were submitted to heat-induced antigen retrieval by covering them with Biocare Reveal Decloaker solution in the Biocare Medical Decloaking Chamber (Biocare Medical, Concord, CA) for 1 minute at 125. Slides were washed with deionized water then Leica Bond Wash solution at room temperature. Slides were incubated with Leica Bond 3% hydrogen peroxide in methanol for 5 minutes to quench endogenous peroxidase activity then washed 3 times with Leica Bond wash solution. Slides were then incubated with the primary antibody, a rabbit monoclonal anti-human Ki-67 (Biocare Medical, clone SP6, Concord, CA; 1/25 for 1 hour) or a non-immune isotype-matched control (isotype negative control rabbit IgG Biocare, Concord, CA). Staining visualization was obtained by incubation with Leica Bond Polymer for 8 minutes followed by Leica Bond DAB Refine for 10 minutes. Counterstaining was done using Leica Bond Hematoxylin for 10 minutes then dehydrated, cleared and cover slipped with a synthetic mounting medium. The stained slides were scanned at 40x using Leica s Aperio eslide Manager on an Aperio AT Turbo scanner and evaluated using HALO image analysis software (Indica Labs, Albuquerque, NM) to determine any differences in the percentage of cells staining positive for Ki67 in rats given GNF2133. The number of proliferating cells (Ki67 positive cells) divided by the total tissue area (the result multiplied by 100) were reported as the percent of proliferating cells per micrometer square of tissue for each animal and the fold (multiple) difference between the values from control and treated animals was determined as an index of GNF2133-induced proliferation within the organs (Figure 6). S51
52 Part VI. Kinase inhibition profiling and Ba/F3 cellular profiling of GNF2133 Table S4. GNF2133 in enzymatic cell free Caliper microfluidic kinase assay a target % inhibition concentration (µm) target % inhibition concentration (µm) Abl MapK AKT MapK AKT MAPK AKT MAPKAPK ALK MAPKAPK AMP-a1b1g MARK AMP-a2b1g MARK ARG MARK ARK MEK AURA MEK AURB MELK AURC MER Axl Met BLK MINK BMX MKNK braf MRCKα BRK MRCKβ BRSK MSK BRSK MSK BTK MSSK CAMK1A MST CAMK1D MST CAMK2A MST CAMK2B MST CAMK2D mtor CAMK2G MUSK CAMK NDR CDK NDR CDK NEK CDK2-cycE Nek CDK3-cycE NEK CDK4-cycD NEK CDK NEK CDK5-p P38b CDK6-cycD P38g CDK p70s6k CDK9-cycT p70s6k S52 (continued on next page)
53 Table S4. (continued) target % inhibition concentration (µm) target % inhibition concentration (µm) CHEK PAK CHEK PAK CK1a PAK CK1-epsilon PAK CK1-γ PAK CK1- γ PAK CK1- γ PAR-1Bα ckit PASK CLK PDGFRα CLK PDGFRβ CLK PDK CLK PERK craf PHKγ CSK PHKγ DAPK PI3Kα DAPK PI4Kβ DCAMKL Pim DDR Pim DDR Pim DYRK1A PKA DYRK1B PKACB DYRK PKCa DYRK PKC-β DYRK PKC-β EGFR PKC-ε EphA PKC-η EphA PKC-γ EphA PKC-ι EphA PKC-θ EphA PKC-ϛ EphA PKN EphB PKN EphB PLK EphB PLK EphB PLK ErbB PRAK ErbB PRKACA FAK PRKD (continued on next page) S53
54 Table S4. (continued) target % inhibition concentration (µm) target % inhibition concentration (µm) FER PRKD FES PRKD FGFR PRKG FGFR PRKG FGFR PRKX FGFR PTK FGR PYK Flt Ret Flt RIPK Flt ROCK FMS ROCK Fyn RON GRK ROS GRK RSK GSK3α RSK GSK3β RSK HASPIN 65 2 RSK HCK SGK HIPK SGK HIPK SGK HIPK SLK HIPK SNF1LK IGF1R SNF1LK IKKα SPHK IKKβ SPHK IKKe SRC InsR SRMS Irak SRPK Irak SRPK IRR STK ITK SYK JAK TAK1-TAB JAK TAOK JAK TAOK Jnk TBK Jnk Tec Jnk TIE (continued on next page) S54
55 Table S4. (continued) target % inhibition concentration (µm) target % inhibition concentration (µm) KDR TNIK LATS TNK LATS TrkA Lck TrkB LOK TrkC LRRK2(G2019S) TSSK LTK TSSK Lyn TTK LynB 10 2 TXK MAP4K TYK MAP4K TYRO MAP4K YES MapK ZAP a GNF2133 was screened at 0.2 or 2.0 µm against 250 kinases. Results were reported as %inhibition, where larger values indicate stronger inhibition. S55
56 Table S5. GNF2133 in Ba/F3 Cellular Kinase Profiling Ba/F3 IC 50 (μm) Ba/F3 IC 50 (μm) BaF3 Parental KDR BCRABL >10.7 KITQ BRAF-V600E >10.7 LCK Jak2_clone1_CTG LYN Jak2_V617F_EpoR_CTG MER KIF5B-RETV804M >10 MET KRasG12V_CTG PDGFRa-Q NPM-ALK PDGFRb Blk RETQ1 >10 BMX RETQ EPHB RON FGFR ROS FGFR SRC FGFR3Q SRC FGFR4Q SYK-IS FGR TIE1-Q FLT1Q TRKA-Q3 >10.7 FLT TRKB-Q FMS-Q TRKC-Q IGF1R-N-FL TYRO INSR_ ZAP70S JAK1S Tpr_Met_CTG JAK3-S1.2/sACP 1.42 BAF3/WT >8.722 JAK S56
57 References: S1. Otwinowski, Z.; Minor, W. Processing of X-ray Diffraction Data Collected in Oscillation Mode, Methods in Enzymology, Volume 276: Macromolecular Crystallography, Part A, p , 1997, C.W. Carter, Jr. & R. M. Sweet, Eds., Academic Press (New York). S2. McCoy, A. J.; Grosse-Kunstleve, R. W.; Adams, P. D.; Winn, M. D.; Storoni, L. C.; Read, R. J. Phaser crystallographic software. J Appl. Crystallogr. 2007, 40 (Pt 4), S3. Winn, M. D.; Ballard, C. C.; Cowtan, K. D.; Dodson, E. J.; Emsley, P.; Evans, P. R.; Keegan, R. M.; Krissinel, E. B.; Leslie, A. G. W.; McCoy, A.; McNicholas, S. J.; Murshudov, G. N.; Pannu, N. S.; Potterton, E. A.; Powell, H. R.; Read, R. J.; Vagin A.; Wilson, K. S. Overview of the CCP4 suite and current developments. Acta Cryst. 2011, D67 (Pt4), S4. Adams, P. D.; Afonine, P. V.; Bunkóczi, G.; Chen, V. B.; Davis, I.W.; Echols, N.; Headd, J. J.; Hung, L.-W.; Kapral, G. J.; Grosse-Kunstleve, R. W.; McCoy, A. J.; Moriarty, N. W.; Oeffner, R.; Read, R. J.; Richardson, D. C.; Richardson, J. S.; Terwilliger, T. C.; Zwart, P. H. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Cryst. 2010, D66, S5. Emsley. P.; Lohkamp, B.; Scott, W. G.; Cowtan, K. Features and development of Coot. Acta Cryst. 2010, D66, S6. Bricogne, G.; Blanc, E.; Brandl, M.; Flensburg, C.; Keller, P.; Paciorek, W.; Roversi, P.; Sharff, A.; Smart, O.S.; Vonrhein, C.; Womack, T.O. (2017) BUSTER version X.Y.Z. Cambridge, United Kingdom: Global Phasing Ltd. S7. Smart, O. S.; Womack, T. O.; Flensburg, C.; Keller, P.; Paciorek, W.; Sharff, A.; Vonrhein, C.; Bricogne, G. Exploiting structure similarity in refinement: automated NCS and targetstructure restraints in BUSTER. Acta Cryst. 2012, D68, S57
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