4F09

Discovery and Optimization of C-2 Methyl Imidazo-pyrrolopyridines as Potent and Orally Bioavailable JAK1 Inhibitors with Selectivity over JAK2

X-RAY DIFFRACTION

Crystallization

Crystalization Experiments
ID	Method	pH	Temperature	Details
1		6	277	0.2 M ammonium acetate, 0.1M sodium citrate pH6, 20 % PEG 8000, VAPOR DIFFUSION, HANGING DROP, temperature 277K

Crystal Properties
Matthews coefficient	Solvent content
2.22	44.61

Crystal Data

Unit Cell
Length ( Å )	Angle ( ˚ )
a = 44.44	α = 90
b = 69.49	β = 101.17
c = 50.23	γ = 90

Symmetry
Space Group	P 1 21 1

Diffraction

Diffraction Experiment
ID #	Crystal ID	Scattering Type	Data Collection Temperature	Detector	Detector Type	Details	Collection Date	Monochromator	Protocol
1	1	x-ray	100	CCD	ADSC QUANTUM 315r		2010-03-17		SINGLE

Radiation Source
ID #	Source	Type	Wavelength List	Synchrotron Site	Beamline
1	SYNCHROTRON	SSRL BEAMLINE BL7-1		SSRL	BL7-1

Data Collection

Overall
ID #	Resolution (High)	Resolution (Low)	Percent Possible (Observed)	R Merge I (Observed)	Net I Over Average Sigma (I)	Redundancy	Number Reflections (All)	Number Reflections (Observed)	Observed Criterion Sigma (F)	Observed Criterion Sigma (I)	B (Isotropic) From Wilson Plot
1	2.4	50	83.2	0.095	7.9	3.1		13267			18

Highest Resolution Shell
ID #	Resolution (High)	Resolution (Low)	Percent Possible (All)	Percent Possible (Observed)	R Merge I (Observed)	Mean I Over Sigma (Observed)	Redundancy	Number Unique Reflections (All)
1	2.15	2.23	33		0.28		1.6

Refinement

Statistics
Diffraction ID	Structure Solution Method	Cross Validation method	Starting model	Resolution (High)	Resolution (Low)	Number Reflections (Observed)	Number Reflections (R-Free)	Percent Reflections (Observed)	R-Factor (Observed)	R-Work	R-Free	R-Free Selection Details	Mean Isotropic B
X-RAY DIFFRACTION	MOLECULAR REPLACEMENT	THROUGHOUT	PDB ENTRY 2B7A	2.4	49.28	11788	575	99.7	0.198	0.195	0.254	RANDOM	25.24

Temperature Factor Modeling
Anisotropic B[1][1]	Anisotropic B[1][2]	Anisotropic B[1][3]	Anisotropic B[2][2]	Anisotropic B[2][3]	Anisotropic B[3][3]
-6.8197		0.495	2.8708		3.9489

RMS Deviations
Key	Refinement Restraint Deviation
t_other_torsion	19.4
t_omega_torsion	3.03
t_angle_deg	1.21
t_bond_d	0.009
t_dihedral_angle_d
t_incorr_chiral_ct
t_pseud_angle
t_trig_c_planes
t_gen_planes
t_it

RMS Deviations
Key	Refinement Restraint Deviation
t_other_torsion	19.4
t_omega_torsion	3.03
t_angle_deg	1.21
t_bond_d	0.009
t_dihedral_angle_d
t_incorr_chiral_ct
t_pseud_angle
t_trig_c_planes
t_gen_planes
t_it
t_nbd
t_improper_torsion
t_chiral_improper_torsion
t_sum_occupancies
t_utility_distance
t_utility_angle
t_utility_torsion
t_ideal_dist_contact

Non-Hydrogen Atoms Used in Refinement
Non-Hydrogen Atoms	Number
Protein Atoms	2398
Nucleic Acid Atoms
Solvent Atoms	91
Heterogen Atoms	19

Software

Software
Software Name	Purpose
DENZO	data reduction
SCALEPACK	data scaling
PHASER	phasing
BUSTER-TNT	refinement
PDB_EXTRACT	data extraction
BUSTER	refinement

RCSB PDB Core Operations are funded by the National Science Foundation (DBI-1832184), the US Department of Energy (DE-SC0019749), and the National Cancer Institute, National Institute of Allergy and Infectious Diseases, and National Institute of General Medical Sciences of the National Institutes of Health under grant R01GM133198.