PO Box 9242, South Yarra, VIC, 3141, Australia +61 0431091329 www.reagency.co

RGNCY-0013 (Glucocorticoid Resistance Inhibitor J9)

Systematic Name: 4-cyclopropyl-5-(pyridin-4-yl)pyrimidin-2-amine Molecular Weight:

212.26

Molecular Formula:

C12H12N4

SMILES: NC1=NC(C2CC2)=C(C3=CC=NC=C3)C=N1 Purity: 99.9% Batch No: R13-1-15

Description This compound (J9) was selected for its lead-like properties at restoring sensitivity to glucocorticoid resistant T-ALL cells (CUTLL1 cell line) through the upregulation of the glucocorticoid receptor. Patients can develop glucocorticoid resistance rendering the treatment ineffective. This compound and its mechanism of action provides a useful strategy for overcoming this resistance. The EC50 of J9 in combination with destramethasone is 28 µM.

-2-

PO Box 9242, South Yarra, VIC, 3141, Australia +61 0431091329 www.reagency.co

References Alexandra M. Cantley, Matthew Welsch, Alberto Ambesi-Impiombato, Marta Sanchez-Martin, Mi-Yeon Kim, Andras Bauer, Adolfo Ferrando, and Brent R. Stockwell. “Small Molecule that Reverses Dexamethasone Resistance in T-cell Acute Lymphoblastic Leukemia (T-ALL).” ACS Medicinal Chemistry Letters 5.7 (2014): 754-759 *Compound J9

Analytical Data

-3-

PO Box 9242, South Yarra, VIC, 3141, Australia +61 0431091329 www.reagency.co

8.677 8.673 8.666 8.662

8.071

7.362 7.358 7.351 7.347 7.271

5.065

1.973 1.966 1.953 1.941

1.236 1.227 1.219 1.216 1.208 1.199 0.975 0.967 0.959 0.946 0.939 -0.000

2.0

0

0.9

4

1.9

6 2

.03

1.0

6

1.9

9 2

.02

108

64

20

PP

M

D:\N

UTS

\DA

TA\$

MC

0919

2-03

6-1_

1.1

, ,

12:3

8:44

.988

+08

00 n

mrs

u@E

P-1

0021

573

US

ER

: nm

rsu

SO

LVE

NT:

CD

Cl3

Exp

erim

ent =

zg3

0P

ulse

leng

th =

13

.360

use

cR

ecyc

le d

elay

=

1.0

00 s

ecN

A =

8S

olve

nt =

CD

Cl3

PTS

1d =

655

36

F1 =

400

.140

015

MH

zF2

=

1.00

0000

MH

zS

W1

=

8223

.68

Hz

AT1

=

7.97

sec

Hz

per P

t 1st

D =

0.

13 H

z S

W2

=

1.

00 H

z H

z pe

r Pt 2

ndD

=

1.00

Hz

O1

=

246

5.97

14 H

z O

2 =

-1.0

000

Hz

LB1

= 0

.30

H

z TP

A

=

0.00

B =

0.

00

C =

0.

00

N

N

H2N

N

MC

0919

2-03

6-1

-4-

PO Box 9242, South Yarra, VIC, 3141, Australia +61 0431091329 www.reagency.co

9 8 7 6 5 4 3 2 1 ppm

−0.000

0.880

0.894

0.930

0.940

0.947

0.960

0.967

0.976

0.993

1.013

1.162

1.174

1.200

1.208

1.216

1.219

1.227

1.237

1.248

1.254

1.273

1.867

1.921

1.933

1.941

1.952

1.964

1.972

1.984

5.034

7.268

7.347

7.350

7.358

7.362

8.071

8.662

8.665

8.673

2.24

2.26

1.01

2.09

2.00

0.96

2.00

PC 1.00GB 0LB 0.30 HzSSB 0WDW EMSF 400.1400060 MHzSI 65536F2 − Processing parameters

SFO1 400.1424710 MHzPLW1 15.00000000 WP1 13.36 usecNUC1 1H======== CHANNEL f1 ========

D1 1.00000000 secTE 295.5 KDE 6.50 usecDW 60.800 usecRG 128AQ 1.9923444 secFIDRES 0.250967 HzSWH 8223.685 HzDS 2NS 8SOLVENT CDCl3TD 32768PULPROG zg30PROBHD 5 mm PABBO BB−INSTRUM spectTime 16.46Date_ 20141223F2 − Acquisition Parameters

PROCNO 1EXPNO 1NAME QC−MC09192−036−1Current Data Parameters

-5-

PO Box 9242, South Yarra, VIC, 3141, Australia +61 0431091329 www.reagency.co

9 8 7 6 5 4 3 2 1 ppm

−0.000

0.834

0.853

0.870

0.905

0.914

0.922

0.934

0.942

0.949

0.966

0.986

1.020

1.032

1.058

1.065

1.075

1.082

1.092

1.232

1.258

1.898

1.910

1.918

1.929

1.940

1.949

1.961

2.333

2.503

2.506

3.340

6.691

7.453

7.456

7.464

7.468

8.088

8.611

8.622

2.15

2.15

1.08

2.14

2.12

0.99

2.00

PC 1.00GB 0LB 0.30 HzSSB 0WDW EMSF 400.1400006 MHzSI 65536F2 − Processing parameters

SFO1 400.1424710 MHzPLW1 15.00000000 WP1 13.36 usecNUC1 1H======== CHANNEL f1 ========

D1 1.00000000 secTE 295.7 KDE 6.50 usecDW 60.800 usecRG 114AQ 1.9923444 secFIDRES 0.250967 HzSWH 8223.685 HzDS 2NS 8SOLVENT DMSOTD 32768PULPROG zg30PROBHD 5 mm PABBO BB−INSTRUM spectTime 14.42Date_ 20141224F2 − Acquisition Parameters

PROCNO 1EXPNO 1NAME QC−MC09192−036−1−DMSOCurrent Data Parameters

-6-

PO Box 9242, South Yarra, VIC, 3141, Australia +61 0431091329 www.reagency.co

9 8 7 6 5 4 3 2 1 ppm

−0.000

0.909

0.945

0.954

0.962

0.974

0.982

0.990

1.007

1.028

1.049

1.108

1.151

1.162

1.188

1.196

1.207

1.215

1.224

1.249

1.260

1.283

1.937

1.948

1.957

1.968

1.979

1.988

2.000

3.220

3.307

4.878

7.512

7.527

7.823

8.046

8.100

8.265

8.578

8.593

2.21

2.05

0.99

2.02

0.94

2.00

PC 1.00GB 0LB 0.30 HzSSB 0WDW EMSF 400.1400085 MHzSI 65536F2 − Processing parameters

SFO1 400.1424710 MHzPLW1 15.00000000 WP1 13.36 usecNUC1 1H======== CHANNEL f1 ========

D1 1.00000000 secTE 295.7 KDE 6.50 usecDW 60.800 usecRG 128AQ 1.9923444 secFIDRES 0.250967 HzSWH 8223.685 HzDS 2NS 8SOLVENT MeODTD 32768PULPROG zg30PROBHD 5 mm PABBO BB−INSTRUM spectTime 14.46Date_ 20141224F2 − Acquisition Parameters

PROCNO 1EXPNO 1NAME QC−MC09192−036−1−MeODCurrent Data Parameters

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PO Box 9242, South Yarra, VIC, 3141, Australia +61 0431091329 www.reagency.co

2014-12-23 13:08:13 1 / 1

D:\Data\user\MC09192-036-1.lcd

Shimadzu MS Report

Rt=0.447min Positive

m/z

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

1100000

1200000

1300000

1400000

1500000

1600000

1700000

1800000

1900000

100 200 300 400 500 600 700 800 900

212.

321

3.0

MSData File : MC09192-036-1.lcd Date Acquired : 12/23/2014 10:53:03 AMInjection Volume : 2 Tray# : 1Vial# : 23 Method File : A90B10+-.lcm

Sample Information

Mass Spectrum

-8-

PO Box 9242, South Yarra, VIC, 3141, Australia +61 0431091329 www.reagency.co

=====================================================================Acq. Operator : xxyan Seq. Line : 5Acq. Instrument : Instrument 1 Location : Vial 43Injection Date : 12/23/2014 4:59:13 PM Inj : 1 Inj Volume : 1 µlDifferent Inj Volume from Sequence ! Actual Inj Volume : 0.5 µlAcq. Method : E:\CHEM32\METHODS\M-A90B10.MLast changed : 12/23/2014 4:44:02 PM by xxyan (modified after loading)Analysis Method : E:\CHEM32\METHODS\WAITING-N.MLast changed : 12/23/2014 5:17:10 PM by xxyan (modified after loading)Method Info : Phenomenenex Gemini C18 5µm,150x4.6 mm Column, Mobile phase:B: 0.1%NH3.H2O in ACN, A: 0.1%NH3.H2O in H2O

min0 2 4 6 8 10 12 14

mAU

0

100

200

300

400

DAD1 A, Sig=254,8 Ref=off (141223\AM000005.D)

4.4

97

5.8

22

7.1

69

8.8

19

9.7

47

11.

516

===================================================================== Area Percent Report ===================================================================== Sorted By : SignalMultiplier : 1.0000Dilution : 1.0000Use Multiplier & Dilution Factor with ISTDs Signal 1: DAD1 A, Sig=254,8 Ref=off Peak RetTime Type Width Area Height Area # [min] [min] [mAU*s] [mAU] %----|-------|----|-------|----------|----------|--------| 1 4.497 BB 0.0395 8.02582e-2 3.40582e-2 4.252e-3 2 5.822 BB 0.0581 2.06424e-1 5.22605e-2 0.0109 3 7.169 BB 0.0617 1885.47498 481.23981 99.9019 4 8.819 BB 0.0666 2.01874e-1 4.47573e-2 0.0107 5 9.747 BB 0.0771 3.43788e-1 6.56858e-2 0.0182 6 11.516 BB 0.1161 1.01974 1.26449e-1 0.0540 Totals : 1887.32706 481.56302 ===================================================================== *** End of Report ***

Data File E:\CHEM32\DATA\2014\141223\AM000005.D Sample Name: QC-MC09192-036-1

Instrument 1 12/23/2014 5:17:30 PM xxyan Page 1 of 1

-9-

PO Box 9242, South Yarra, VIC, 3141, Australia +61 0431091329 www.reagency.co

=====================================================================Acq. Operator : xxyan Seq. Line : 5Acq. Instrument : Instrument 1 Location : Vial 43Injection Date : 12/23/2014 4:59:13 PM Inj : 1 Inj Volume : 1 µlDifferent Inj Volume from Sequence ! Actual Inj Volume : 0.5 µlAcq. Method : E:\CHEM32\METHODS\M-A90B10.MLast changed : 12/23/2014 4:44:02 PM by xxyan (modified after loading)Analysis Method : E:\CHEM32\METHODS\WAITING-N.MLast changed : 12/23/2014 5:18:13 PM by xxyan (modified after loading)Method Info : Phenomenenex Gemini C18 5µm,150x4.6 mm Column, Mobile phase:B: 0.1%NH3.H2O in ACN, A: 0.1%NH3.H2O in H2O

min0 2 4 6 8 10 12 14

mAU

0

100

200

300

400

500

600

700

DAD1 B, Sig=214,8 Ref=off (141223\AM000005.D)

7.1

69

11.

072

11.

274

12.

019

===================================================================== Area Percent Report ===================================================================== Sorted By : SignalMultiplier : 1.0000Dilution : 1.0000Use Multiplier & Dilution Factor with ISTDs Signal 1: DAD1 B, Sig=214,8 Ref=off Peak RetTime Type Width Area Height Area # [min] [min] [mAU*s] [mAU] %----|-------|----|-------|----------|----------|--------| 1 7.169 BB 0.0617 3204.43921 817.26477 99.7854 2 11.072 BV 0.0567 5.87892e-1 1.77378e-1 0.0183 3 11.274 VB 0.1289 3.93030 3.92202e-1 0.1224 4 12.019 BV 0.0924 2.37444 3.93721e-1 0.0739 Totals : 3211.33184 818.22807 ===================================================================== *** End of Report ***

Data File E:\CHEM32\DATA\2014\141223\AM000005.D Sample Name: QC-MC09192-036-1

Instrument 1 12/23/2014 5:18:19 PM xxyan Page 1 of 1