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- PDB-9e5f: Discovery of an Orally Bioavailable KRAS G12D Inhibitor -

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Basic information

Entry
Database: PDB / ID: 9e5f
TitleDiscovery of an Orally Bioavailable KRAS G12D Inhibitor
ComponentsGTPase KRas
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Inhibitor / Oncoprotein / GTPase / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


forebrain astrocyte development / negative regulation of epithelial cell differentiation / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / Rac protein signal transduction / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants ...forebrain astrocyte development / negative regulation of epithelial cell differentiation / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / Rac protein signal transduction / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / Signalling to RAS / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / glial cell proliferation / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by CSF3 (G-CSF) / Signaling by FGFR4 in disease / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / protein-membrane adaptor activity / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / Tie2 Signaling / positive regulation of glial cell proliferation / FRS-mediated FGFR1 signaling / homeostasis of number of cells within a tissue / Signaling by FGFR2 in disease / striated muscle cell differentiation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Downstream signal transduction / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in ERBB2 signaling / Insulin receptor signalling cascade / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / small monomeric GTPase / FCERI mediated MAPK activation / RAF activation / regulation of long-term neuronal synaptic plasticity / Signaling by ERBB2 TMD/JMD mutants / Signaling by high-kinase activity BRAF mutants / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / visual learning / Signaling by ERBB2 KD Mutants / cytoplasmic side of plasma membrane / Regulation of RAS by GAPs / RAS processing / Signaling by CSF1 (M-CSF) in myeloid cells / Signaling by RAF1 mutants / Negative regulation of MAPK pathway / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / GDP binding / Signaling by BRAF and RAF1 fusions / MAPK cascade / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / G protein activity / actin cytoskeleton organization / Ca2+ pathway / RAF/MAP kinase cascade / neuron apoptotic process / gene expression / negative regulation of neuron apoptotic process / mitochondrial outer membrane / Ras protein signal transduction / Golgi membrane / focal adhesion / GTPase activity
Similarity search - Function
Small GTPase, Ras-type / small GTPase Ras family profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Small GTP-binding protein domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.35 Å
AuthorsDeller, M.C. / Epling, L.B.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery of INCB159020, an Orally Bioavailable KRAS G12D Inhibitor.
Authors: Ye, Q. / Shvartsbart, A. / Li, Z. / Gan, P. / Policarpo, R.L. / Qi, C. / Roach, J.J. / Zhu, W. / McCammant, M.S. / Hu, B. / Li, G. / Yin, H. / Carlsen, P. / Hoang, G. / Zhao, L. / Susick, R. ...Authors: Ye, Q. / Shvartsbart, A. / Li, Z. / Gan, P. / Policarpo, R.L. / Qi, C. / Roach, J.J. / Zhu, W. / McCammant, M.S. / Hu, B. / Li, G. / Yin, H. / Carlsen, P. / Hoang, G. / Zhao, L. / Susick, R. / Zhang, F. / Lai, C.T. / Allali Hassani, A. / Epling, L.B. / Gallion, A. / Kurzeja-Lipinski, K. / Gallagher, K. / Roman, V. / Farren, M.R. / Kong, W. / Deller, M.C. / Zhang, G. / Covington, M. / Diamond, S. / Kim, S. / Yao, W. / Sokolsky, A. / Wang, X.
History
DepositionOct 28, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 22, 2025Provider: repository / Type: Initial release
Revision 1.1Feb 5, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,3974
Polymers19,3871
Non-polymers1,0113
Water2,810156
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)40.175, 53.63, 90.206
Angle α, β, γ (deg.)90, 90, 90
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein GTPase KRas / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras


Mass: 19386.848 Da / Num. of mol.: 1 / Fragment: residues 1-169 / Mutation: G12D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P01116, small monomeric GTPase
#2: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#3: Chemical ChemComp-A1BEJ / (4P)-4-{1-[(1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl]-8-chloro-4-[3-(dimethylamino)azetidin-1-yl]-6-fluoro-1H-imidazo[4,5-c]quinolin-7-yl}naphthalen-2-ol


Mass: 543.034 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H28ClFN6O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 156 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.45 Å3/Da / Density % sol: 49.85 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.1 M Sodium acetate, pH 4.6,30% PEG 4000 and 0.2M ammonium acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 18, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.35→53.63 Å / Num. obs: 43420 / % possible obs: 99.5 % / Redundancy: 12.6 % / Biso Wilson estimate: 12.9 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.04 / Rpim(I) all: 0.01 / Rrim(I) all: 0.04 / Net I/σ(I): 26.4
Reflection shellResolution: 1.35→1.37 Å / Redundancy: 9 % / Rmerge(I) obs: 0.3 / Mean I/σ(I) obs: 3.7 / Num. unique obs: 2023 / CC1/2: 0.96 / Rpim(I) all: 0.1 / Rrim(I) all: 0.32 / % possible all: 95.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0425refinement
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.35→46.099 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.961 / SU B: 1.414 / SU ML: 0.027 / Cross valid method: FREE R-VALUE / ESU R: 0.052 / ESU R Free: 0.048
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.1782 2120 4.889 %
Rwork0.1535 41239 -
all0.155 --
obs-43359 99.404 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 18.98 Å2
Baniso -1Baniso -2Baniso -3
1--0.038 Å2-0 Å20 Å2
2---0.598 Å2-0 Å2
3---0.636 Å2
Refinement stepCycle: LAST / Resolution: 1.35→46.099 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1371 0 40 156 1567
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0121485
X-RAY DIFFRACTIONr_bond_other_d0.0050.0161364
X-RAY DIFFRACTIONr_angle_refined_deg2.0071.842033
X-RAY DIFFRACTIONr_angle_other_deg1.1041.7863147
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9685183
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.859.28614
X-RAY DIFFRACTIONr_dihedral_angle_other_2_deg7.62851
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.53610255
X-RAY DIFFRACTIONr_dihedral_angle_6_deg16.3561070
X-RAY DIFFRACTIONr_chiral_restr0.1150.2228
X-RAY DIFFRACTIONr_gen_planes_refined0.0160.021750
X-RAY DIFFRACTIONr_gen_planes_other0.0050.02332
X-RAY DIFFRACTIONr_nbd_refined0.2130.2269
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1480.21218
X-RAY DIFFRACTIONr_nbtor_refined0.1730.2735
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0690.2793
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1040.2112
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1740.216
X-RAY DIFFRACTIONr_nbd_other0.2160.230
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1150.26
X-RAY DIFFRACTIONr_mcbond_it3.0770.807699
X-RAY DIFFRACTIONr_mcbond_other3.0760.807699
X-RAY DIFFRACTIONr_mcangle_it4.7221.458878
X-RAY DIFFRACTIONr_mcangle_other4.721.457879
X-RAY DIFFRACTIONr_scbond_it4.5081.053786
X-RAY DIFFRACTIONr_scbond_other4.5061.053787
X-RAY DIFFRACTIONr_scangle_it6.4621.8431146
X-RAY DIFFRACTIONr_scangle_other6.461.8431147
X-RAY DIFFRACTIONr_lrange_it12.611.1281755
X-RAY DIFFRACTIONr_lrange_other11.98810.5111726
X-RAY DIFFRACTIONr_rigid_bond_restr4.05232849
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
1.35-1.3850.1681470.15828850.15931840.9810.98695.22610.13
1.385-1.4230.1731630.14429220.14530890.980.98899.87050.118
1.423-1.4640.1791200.13228760.13429990.9790.98999.90.107
1.464-1.5090.1521470.1227610.12229180.9860.99199.65730.098
1.509-1.5590.1481530.10827130.1128680.9860.99399.93030.089
1.559-1.6130.1291440.10426110.10627660.9880.99399.60230.087
1.613-1.6740.1311310.1125360.11126700.9890.99299.88760.093
1.674-1.7420.1491190.11424130.11525360.9850.99299.84230.098
1.742-1.820.1591320.12223350.12424710.9840.99199.83810.106
1.82-1.9080.1751120.13422530.13623720.980.98999.70490.119
1.908-2.0110.1671000.15121350.15222410.9830.98799.73230.14
2.011-2.1330.1911020.1620200.16121230.9790.98699.95290.152
2.133-2.280.176920.14719180.14820190.9810.98899.55420.144
2.28-2.4620.17950.14417600.14618690.9830.98799.25090.146
2.462-2.6970.156800.15816770.15817590.9840.98499.88630.164
2.697-3.0140.209770.17114970.17215740.9710.9821000.183
3.014-3.4770.195760.17513180.17614030.9770.98199.35850.195
3.477-4.2530.211570.16511490.16712090.9780.98499.75190.196
4.253-5.9890.195530.1849160.1849700.9840.98699.89690.223
5.989-46.0990.213190.2145440.2145780.9810.9797.40480.27
Refinement TLS params.Method: refined / Origin x: 17.6656 Å / Origin y: -2.5757 Å / Origin z: -12.6038 Å
111213212223313233
T0.0234 Å20.0118 Å20.0051 Å2-0.0207 Å20.0035 Å2--0.0029 Å2
L2.273 °20.3088 °2-0.2848 °2-2.0296 °2-0.5891 °2--2.2197 °2
S-0.0386 Å °-0.059 Å °0.0476 Å °-0.1149 Å °0.034 Å °-0.0013 Å °0.0901 Å °-0.0819 Å °0.0046 Å °
Refinement TLS groupSelection: ALL

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