SUPPLEMENTAL TABLES. Spectrum and Degree of CDK Drug Interactions Predicts Clinical Performance
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1 SUPPLEMENTAL TABLES Spectrum and Degree of CDK Drug Interactions Predicts Clinical Performance Ping Chen 1, Nathan V. Lee 2, Wenyue Hu 3, Meirong Xu 2, Rose Ann Ferre 1, Hieu Lam 2, Simon Bergqvist 2, James Solowiej 2, Wade Diehl 1, You-Ai He 1, Xiu Yu 1, Asako Nagata 1, Todd VanArsdale 2, Brion W. Murray 2 1 Oncology Medicinal Chemistry, Pfizer Worldwide Research and Development, Science Center Drive, San Diego, CA Oncology Research Unit, Pfizer Worldwide Research and Development, Science Center Drive, San Diego, CA Drug Safety, Pfizer Worldwide Research and Development, Science Center Drive, San Diego, CA
2 Table S1. Statistics for the crystallographic analysis. Crystal Palbociclib Abemaciclib Ribociclib Dinaciclib CDK6 CDK6 CDK6 CDK2/CyclinE Internal merging and scaling Resolution (Å) Reflections measured Unique reflection Completeness (%) 100 (99.9) 100 (99.6) 99.9 (99.3) 99.9 (99.7) Average I/σ 14.6 (1.4) 26.2 (2.0) 32.1 (2.4) 22.9 (3.5) R 1 mrg (%) 3.2 (54.1) 3.9 (53.4) 3.2 (60.8) 6.5 (60.7) Refinement statistics Resolution range (Å) Reflections used Total nonhydrogen atoms Rcryst 3 (%) Rfree 4 (%) rmsd from ideal bond length (Å) rmsd from ideal bond angle ( ) Average B (Å 2 ; all atoms) Data for the outermost resolution shell are given in parentheses. 1 R mrg = Sum( Ihl - < Ih > )/Sum(< Ih >) 2 Number of reflections used in working set. 3 Rcryst = Fobs - Fcalc / Fobs, where summation is over data used in the refinement. 4 Rfree is the same calculation including the 9% of data excluded from all refinements. 2
3 Table S2. Biochemical and cellular potencies of the second generation CDK-directed drug AG Biochemical potency is defined by the equilibrium constant that describes binding affinity (K i ). Phosphorylation of prb was monitored in two ER+ tumor cell lines to measure pharmacodynamic effects. Analysis AG Biochemical PD in Cells CDK1/cyclinA 2 K i (nm) CDK2/cyclinE 1 K i (nm) CDK4/cyclinD 3 K i (nm) CDK5/p35 K i (nm) CDK6/cyclinD 1 K i (nm) CDK7/cyclinH/MAT1 K i (nm) CDK9/cyclinT 1 K i (nm) MCF7 IC 50 (nm) prb-ser ± 0.01 (n=4) 0.11 ± 0.01 (n=13) 1.9 ± 0.1 (n=16) 0.14 ± 0.03 (n=8) 1.3 ± 0.1 (n=6) 4.3 ± 0.3 (n=5) 1.6 ± 0.1 (n=12) 103 ± 21 (n=3) 3
4 Table S3. In vitro analysis of binding potency of abemaciclib, dinaciclib, and palbociclib to non-kinase proteins. A panel of 17 non-kinase proteins was performed by CEREP using ligand displacement assays. These assays encompass a diverse range of functional proteins. Target Endpoint Abemaciclib Dinaciclib Palbociclib Adren Alpha 1a EC 50 (μm) >10000 >10000 >10000 Dopamine 1 EC 50 (μm) >10000 >10000 >10000 Histamine 1 EC 50 (μm) >10000 >10000 >10000 Muscarinic 1 EC 50 (μm) >10000 >10000 > HT2b EC 50 (μm) >10000 >10000 >10000 Adren Beta 2 EC 50 (μm) >10000 >10000 >10000 Cannabinoid 1 EC 50 (μm) >10000 >10000 >10000 Mu Opioid EC 50 (μm) >10000 >10000 >10000 SERT IC 50 (μm) >10000 >10000 >10000 DAT IC 50 (μm) >10000 >10000 >10000 NET IC 50 (μm) >10000 >10000 >10000 PDE3A1 IC 50 (μm) 1600 > PDE4D3 IC 50 (μm) PDE5A1 IC 50 (μm) L-Type Calcium EC 50 (μm) >20000 >20000 >20000 Sodium (Nav1.5) EC 50 (μm) >10000 >10000 >10000 BRD4 IC 50 (μm) >25000 >25000 >
5 Table S4. Broad kinase selectivity of selective CDK4/6 drugs. Drugs were tested at 1 μm in the Carna Biosciences mobility shift kinase assay (Carna Biosciences). 274 human kinases analyzed at a K m concentration of ATP with the kinase inhibited by over 50% are tabulated except AG which >70% is used. Cyclin-dependent kinases are highlighted in magenta. Abemaciclib (1 µm) Dinaciclib (1 µm) Palbociclib (1 µm) Ribociclib (1 µm) AG (1 µm) CaMK2δ CDK3/CycE CDK4/CycD CDK4/CycD CDK2/CycE CaMK2α 99.4 CDK5/p CDK6/CycD CDK6/CycD CDK9/CycT CaMK2β 99.2 CDK1/CycB CLK CaMK2β 83.9 TRKB PIM CDK2/CycA HIPK CaMK2δ 82.5 CLK CaMK2γ 98.4 CDK9/CycT MAP2K5_Cascade 84.8 QIK 77.6 CDC2/CycB CDK2/CycA CDK7/CycH/MAT FLT CaMK2γ 67.6 FLT DYRK1A 98.3 CDK2/CycE Erk TNK MARK GSK3α 98.0 CDK6/CycD TRKA 72.7 GSK3β PIM CDK4/CycD CLK GSK3α CDK9/CycT CLK PKD MST GSK3β 96.5 Erk PKD CDK2/CycA DYRK1B 96.2 GSK3β 71.6 PKR 71.4 MARK CLK MAP2K5_Cascade 70.8 DYRK1B 70.5 CDK3/CycE HGK 95.2 DYRK1B 70.2 PKD CLK DYRK GSK3α 67.9 PEK 68.8 SLK 99.5 CLK HIPK HIPK LOK 99.5 CDK6/CycD CLK HIPK MARK HIPK MST NuaK CDK6/CycD IRAK HIPK CDK9/CycT RSK HIPK HIPK HIPK MST PKR 93.8 DYRK1A 52.4 CaMK2δ 54.0 CDK4/CycD CRIK 93.6 TSSK MARK DYRK DYRK TRKA 98.4 HIPK MER 52.2 JAK HIPK TRKC 98.2 PKCα 92.5 MAP4K CDK4/CycD TNIK 97.8 TNIK 91.2 HGK 97.7 PKD CDK7/CycH/MAT PHKG NDR PKD NDR ROS 88.2 NuaK FLT DYRK1B 96.6 PASK 87.5 PDGFRβ 96.2 PKCβ AurA/TPX PKCβ PKD CK2α2/β 86.0 MUSK 95.0 CDK5/p JAK MRCKβ 85.6 RET 93.1 PKD NuaK CK2α1/β 82.0 PKN SGK 81.3 CLK PKCδ 79.2 FLT ROCK PDGFRα 90.5 CDC7/ASK 77.9 QIK 90.5 MUSK 77.2 RSK NEK PKD CDK2/CycE SYK 90.1 PKCθ 74.7 FYN(isoform b) 90.0 MNK FGFR TRKA 69.0 RSK CDK3/CycE ROCK PKN PKD MSK CaMK2δ 84.9 DAPK FGFR PIM AMPKα2/β1/γ PKCη 63.5 YES 84.1 MNK RSK CDK1/CycB PKCδ 83.1 JAK CHK CK1δ 61.7 ITK 82.2 NuaK FGR 81.9 TAOK PKCα 81.5 FER 59.9 MST MRCKα 59.6 MINK 80.5 MINK 58.2 CGK CDK7/CycH/MAT SIK 78.7 LOK 56.5 FLT DDR HIPK SLK 55.7 PAK Haspin 55.5 PKCβ PKCγ 53.5 HIPK AXL 51.5 KDR 76.1 PYK FGFR SRPK MER 74.9 ROCK TSSK AMPKα1/β1/γ HIPK AXL 72.5 MST p70s6k 71.3 AurA 70.6 DDR BRSK
6 Table S5. Biochemical dose-response follow-up was conducted for a subset of kinases inhibited by the three CDK4/6 drugs using a K m concentration of ATP (Carna Biosciences) (CDK proteins excluded). (A) IC 50 values were converted to K i values using the Cheng-Prusoff equation. (B) Calculated inhibition of the kinases at 1 mm ATP and 10 μm drug using the individual K m,atp values determined by the vender using the competitive inhibition equation. A Biochemical Dose-Response Analysis Kinase Abemaciclib K i (nm) Kinase Palbociclib K i (nm) Kinase Ribociclib K i (nm) DYRK1B 0.5 CLK1 16 CaMK2δ 138 HIPK2 0.9 FLT3 53 CaMK2β 147 CaMK2δ 2.5 HIPK2 70 QIK 161 DYRK3 3.6 MAP2K5_Cascade 90 HIPK3 4.5 Erk5 129 CLK1 5.2 DYRK1B 162 DYRK1A 5.4 CLK2 176 DYRK2 5.5 PKD3 204 CaMK2β 6.2 PKR 241 CaMK2γ 6.2 PKD2 277 PIM1 7.7 PIM3 8.5 GSK3α 9.1 HIPK1 12 CaMK2α 19 GSK3β 19 CLK2 20 HGK 32 CRIK 34 PKCα 34 HIPK4 48 IRAK1 48 PKR 49 PKD2 76 TNIK 98 B Estimation of Kinase Inhibition at 1 mm ATP by 10 μm Drug Kinase K m,atp Abemaciclib K i (nm) % Inhibition Kinase K m,atp Palbociclib K i (nm) % Inhibition Kinase K m,atp Ribociclib K i (nm) % Inhibition DYRK1B CLK CaMK2δ HIPK FLT CaMK2β CaMK2δ HIPK QIK DYRK MAP2K5_Cascade? 90 HIPK Erk CLK DYRK1B DYRK1A CLK DYRK PKD CaMK2β PKR CaMK2γ PKD PIM PIM GSK3α HIPK CaMK2α GSK3β CLK HGK CRIK PKCα HIPK IRAK PKR PKD TNIK
7 Table S6. Kinase selectivity toward endogenous human kinases using irreversible ATP analog target engagement assay. (A) Two cell lines were used to maximize coverage of the human kinome (259 human kinases detected). CDK4/6 drugs were screened at 100 nm. Multiple kinase fragments can be determined in the assay so independent assessments are reported. Some kinase peptides can be from different kinases and the ambiguity is noted in the table. (B) Target engagement of palbociclib in MCF7 breast cancer cells (C) Dose-response analysis with palbociclib in Colo205 tumor cells. (ND is not detected). A Abemaciclib (0.1 μm) Palbociclib (0.1 μm) Ribociclib (0.1 μm) Kinase PC3 cells THP1 cells Kinase PC3 cells THP1 cells Kinase PC3 cells THP1 cells GSK3α MPSK CDK GSK3β MPSK MAP2K MPSK CLK1 42 ND CaMK2γ CDK CDK CDK9 3 ND CaMK2δ CaMK2α,CaMK2β,CaMK2δ,CaMK2γ CDK16, CDK CDK PIP5K CDK CaMK2β CLK1 46 ND CDK PDHK1 40 ND CDK CaMKK CLK CDK17, CDK CDK PKCα,PKCβ 34 ND B Palbociclib (1 µm) Kinase MCF7 cells CDK CDK6 ND MPSK1/STK PIK3C3 65 CDK JNK CDK PIP4K2C 55.5 CDK16/CDK CDK17/CDK C Kinase Palbociclib in Colo205 cells IC µm 1 µm 0.1 µm 0.01 µm (µm) CDK MPSK1/STK16 >95 > CDK PIP4K2C PIK3C CDK CDK CDK16/ JNK CaMK2d CDK17/ CaMK2α/β/δ/γ JNK1/2/ CDK PKR PKR CaMKK PEK PIP5K >10 PYK >10 LOK >10 SLK >10 PKD >10 CDK >10 PIP4K2A >10 RSK2 domain >10 7
8 Table S7. Biochemical potencies of selective CDK4/6 drugs palbociclib (PD ), ribociclib (LEE011), abemaciclib (LY ), and dinaciclib (SCH ) from Carna Biosciences. The IC 50 potency values may under-represent true drug affinity because timedependence and tight-binding inhibition are not factored into the analysis. IC 50 (nm) Abemaciclib Dinaciclib Palbociclib Ribociclib CDK4/CyclinD CDK6/CyclinD CDK1/CyclinB >3000 >3000 CDK2/CyclinA >3000 CDK2/CyclinE >3000 >3000 CDK3/CyclinE >3000 >3000 CDK5/p >3000 CDK7/CyclinH/MAT >3000 >3000 CDC7/ASK 180 >3000 >3000 >3000 CDK9/CyclinT
9 Table S8. Human pharmacokinetic properties of CDK-targeted drugs. Human Pharmacokinetic Parameters Abemaciclib Palbociclib Ribociclib Dinaciclib Dose 200 mg Q12H 125 mg QD 600 mg QD 80 mg every 21d AUC 0-24 steadystate (h*ng/ml) ( ) 5520 a 1733 b >20000 c 4193 d C max (ng/ml) 298 a 97.4 b ~3000 c 1330 d ( ) MW a b c d C ave (nm) (total) > C max (nm) (total) Fraction unbound Fu (%) e Unbound C ave (nm) > Unbound C max (nm) (1) a, (2) b, (3) c, (4, 5) d, e human plasma protein binding analysis by equilibrium dialysis 9
10 Table S9. Isothermal titration calorimetry results for CDK-directed drugs binding to CDK6 in the absence of cyclin D. Compound n K d (nm) G (kcal mole -1 ) H (kcal mole -1 ) -T S (kcal mole -1 ) Abemaciclib 1.3 ± ± ± Dinaciclib 0.8 ± ± ± Palbociclib 1.0 ± ± ± Ribociclib 1.0 ± ± ± Equilibrium dissociation constant (K d ), binding stoichiometry (n), and enthalpy change ( H) were measured by ITC. Free energy change ( G) and entropy change ( S) were calculated from the K d and H at 20 o C. Standard deviations were determined from 3 4 repeat experiments. 10
11 Supplemental References 1. Patnaik A, Rosen LS, Tolaney SM, Tolcher AW, Goldman JW, Gandhi L, et al. Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Other Solid Tumors. Cancer Discov Flaherty KT, Lorusso PM, Demichele A, Abramson VG, Courtney R, Randolph SS, et al. Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD , administered using a 21-day schedule in patients with advanced cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2012;18: Infante JR, Shapiro GI, Witteveen PO, Gerecitano JF, Ribrag V, Chugh R, et al. Phase 1 multicenter, open label, dose-escalation study of LEE011, an oral inhibitor of cyclindependent kinase 4/6, in patients with advanced solid tumors or lymphomas. Molecular cancer therapeutics. 2013;12:A Gojo I, Sadowska M, Walker A, Feldman EJ, Iyer SP, Baer MR, et al. Clinical and laboratory studies of the novel cyclin-dependent kinase inhibitor dinaciclib (SCH ) in acute leukemias. Cancer chemotherapy and pharmacology. 2013;72: Mita MM, Joy AA, Mita A, Sankhala K, Jou YM, Zhang D, et al. Randomized phase II trial of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus capecitabine in patients with advanced breast cancer. Clin Breast Cancer. 2014;14:
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