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KiNativ® In situ kinase profiling

Stanford University ChEM-H

confidential

@KiNativPlatform

Principle of the KiNativ platform

• ATP (or ADP) acyl phosphate binds to, and covalently modifies

Lysine residues in the active site
• Thus, ATP acyl phosphate with a desthiobiotin tag can be used capture and quantitate kinases in a complex lysate

Acyl phosphate

  • Desthiobiotin tag
  • ATP

2

ATP acyl phosphate probe covalently modifies kinase in the active site

Lysine 2

Lysine 1

3

ATP acyl phosphate probe covalently modifies kinase in the active site

Lysine 2

Lysine 1

4

Samples trypsinized, probe-labeled peptides captured with streptavidin, and analyzed by targeted LC-MS2

  • Identification
  • Quantitation

Explicit determination of peptide sequence and probe modification site from MS2 spectrum
Integration of signal from MS2 fragment ions

5

Comprehensive Coverage of Protein and Lipid Kinases

Protein kinases
Atypical kinases

   
     

Green: Kinases detected on KiNativ Red: Kinases not detected on KiNativ

~80% of known protein and atypical kinases identified on the platform

http://www.kinativ.com/coverage/protein-lipid.html

6

Profiling compound(s) on the KiNativ platform

Control sample – add probe

Sample: Lysate

derived from any

cell line or tissue

Treated sample – add inhibitor followed by probe

from ANY species

Inhibited

kinase

  • Green: Kinases
  • Blue: Probe

Gray: Non-kinases Red: Inhibitor

7

Profiling compound(s) on the KiNativ platform

Control sample – add probe

Sample: Lysate

derived from any

cell line or tissue

Treated sample – add inhibitor followed by probe

from ANY species

Inhibited kinase

Time

8

KiNativ – Displaying processed data

9

KiNativ profiling formats

Lysate

• Compound(s) added to lysate prepared from relevant cell line/tissue

followed by probe

• Efficient approach to determine on-target potency and selectivity

Live cell

• Compound(s) added to cells for a period of time, after which cells are harvested, washed, lysed and probe-labeled

• Confirm cell permeability and compound MOA, i.e., how well does

on-target potency (KiNativ) compare to EC50 values from a cellbased assay

Note: 10X dilution during lysis prior to probe addition, reversible compounds may re-equilibrate with target(s)

Live animal

• Animals treated with compound, after which they are sacrificed, relevant tissues harvested, snap-frozen and sent out for profiling on KiNativ

Recommended 100 mg tissue per sample

10

Why profile compounds on KiNativ – A study of JAK inhibitors

• Compounds profiled in PBMC lysate

  • Upadacitinib*
  • Ruxolitinib*
  • Baricitinib*
  • Tofacitinib*

JAKs

Fedratinib*

  • Filgotinib
  • Abrocitinib
  • Pacritinib

*Clinically approved compounds

11

Why profile compounds on KiNativ – A study of JAK inhibitors

• KiNativ IC50 values for selected JAK inhibitors, PBMC lysate

*Clinically approved compounds

12

Comparing JAK1/TYK2 pIC50 to cell-based pEC50

  • KiNativ
  • Recombinant

Abrocitinib
Ruxolitinib
Filgotinib
Tofacitinib

Pacritinib
Abrocitinib

Ruxolitinib

Baricitinib
Baricitinib
Pacritinib

  • Upadacitinib
  • Upadacitinib

Tofacitinib
Fedratinib

Filgotinib Fedratinib

IC50 and EC50 values within 3-fold

Cell-based assay: Monitor inhibition of INFα dependent pSTAT1 in Jurkat cells

13

Comparing JAK2 pIC50 to cell- based pEC50

  • KiNativ
  • Recombinant

Ruxolitinib
Fedratinib

Pacritinib

Filgotinib
Baricitinib
Tofacitinib
Fedratinib

Tofacitinib
Ruxolitinib

Baricitinib
Filgotinib
Baricitinib

Upadacitinib
Upadacitinib

Pacritinib

Abrocitinib
Abrocitinib

IC50 and EC50 values within 3-fold

Cell-based assay: Monitor inhibition of pSTAT5 in HEL cells

14

Quantifying the selectivity of kinase inhibitors

• One of the main reasons for profiling inhibitors against a panel of kinases is to assess selectivity

• Assessing selectivity can be arbitrary!

Method to quantify selectivity – Selectivity score (S)

• Based on the method described by Piotr Grazcyk “Gini

Coefficient:ꢀ A New Way To Express Selectivity of Kinase

Inhibitors against a Family of Kinases

doi.org/10.1021/jm070562u
• Profile compound at 2-4 doses, estimate IC50s • Convert IC50s to pIC50s and normalize to target pIC50, i.e., on-

target normalized pIC50 = 1

• Plot the normalized IC50s against the targets and determine area under the curve
• Reciprocal of the area under the curve = Selectivity score (S)
(higher the score, more selective the compound)

15

Quantifying Selectivity – JAK inhibitors

• Approved JAK inhibitors had good selectivity scores

Upadacitinib* S = 9.2

• Fedratinib, an approved JAK2 inhibitor for

Tofacitinib*
S = 7.9

Baricitinib*
S = 7.8

myeloproliferative diseases had a surprisingly low

Ruxolitinib* S = 7.0

selectivity score

Abrocitinib# S = 6.0

Off-targets

Filgotinib^

Fedratinib*

Pacritinib^

S = 5.8

S = 3.7

S = 3.0

more potently inhibited than on-target

* Clinically approved compounds # Undergoing clinical trials ^ Failed clinical trials

More potent on-target activity
The steeper the slope,

the fewer off-targets were observed

16

Kinases

Efficacy of Fedratinib may be due to an off-target

• Cell-killing efficacy was

Baricitinib

determined for Baricitinib and Fedratinib in either HEL or Jurkat cells

• HEL cells are driven by constitutively active JAK2 (V617F)

• Jurkat cells are not known to have any aberrations in JAK signaling pathways

HEL Jurkat

Fedratinib

• Baricitinib, a potent JAK2

inhibitor kills HEL cells significantly more potently than Jurkat, while Fedratinib kills HEL and Jurkat cells with similar potencies

17

Profiling the covalent BTK inhibitor Ibrutinib

• Ramos cells were treated with Ibrutinib (10 and 1 µM, and no-inhibitor control) for one hour

• Cells were then washed, harvested and lysed

• Lysate was divided into two parts and either probe-labeled as is, or gelfiltered and then probe-labeled

18

Profiling Ibrutinib in Ramos cells

• Ibrutinib modifies BTK on Cys-481 (highlighted)

• For all kinases that appear to be covalently modified by Ibrutinib, there is a
Cys residue either precisely aligned with BTK Cys-481, or in close proximity

19

Profiling kinases during cell cycle progression

Confluent cells

Profiling kinases in A375 during cell cycle progression (kinase activities compared to 0 h)

Sub-culture

Harvest cells at

various

times after subculturing, analyze by MS

0 h
8 h

32 h

1.5X 0.67X

96 h

Kinases

20

Profiling kinases during cell cycle progression

Confluent cells

Profiling kinases in A375 during cell cycle progression (kinase activities compared to 0 h)

MS Signal ratio

Sub-culture

Increases

Harvest cells at

various

times after subculturing, analyze by MS

0 h
8 h

32 h

96 h

Decreases
• These dynamic changes in the kinome may be modulated by kinase inhibitors
• Long-term treatment of cells with inhibitors might result in the observation of changes in the kinome due to pathway effects, in addition to the direct targets

21

Profiling the CDK4/CDK6 inhibitor Palbociclib, in Colo-205 cells

• Palbociclib is an FDA approved CDK4/CDK6 inhibitor for the treatment of ER-positive and HER2-negative breast cancer

• The compound exhibits a wide-range of potencies in cell-killing assays • The molecular basis determining sensitivity or resistance to the compound is not fully understood

Palbociclib

22

Profiling Palbociclib in either sensitive (Colo205) or resistant (MDA-MB-486) cells – live cell format

Colo205 (sensitive)
1µM Palbociclib
MDA-MB-468 (resistant)
1µM Palbociclib

1.5X

Direct
Direct Indirect

  • Kinases
  • Kinases

Chemoproteomic Evaluation of Target Engagement by the Cyclin-Dependent Kinase 4 and 6 Inhibitor Palbociclib Correlates with Cancer Cell Response

DOI: 10.1021/acs.biochem.6b00629

23

Profiling Palbociclib in either sensitive (Colo205) or resistant (MDA-MB-486) cells – live cell format

• CDK4 is not inhibited in MDA-MB-468 cells, although the other palbociclib targets are inhibited to the same extent

MS Signal ratio [(Treated)/(Control)]

Direct targets

Pathway effects

24

Mechanistic basis for sensitivity/resistance of cells to CDK4/CDK6 inhibitors

• Elevated levels of CDKN2

proteins, but not CDKN1 proteins inhibit both the binding of ATP probe and inhibitor to CDK4 and CDK6

• Observation is consistent with

the fact that CDKN2 proteins bind CDK4 and CDK6, while CDKN1 proteins bind CDK2

MCF7 cells were transfected with either GFP or

various CDKN proteins, lysates were then generated, probe-labeled and analyzed by KiNativ

Direct CDKN2 Modulation of CDK4 Alters Target Engagement of CDK4 Inhibitor Drugs

DOI: 10.1158/1535-7163.MCT-18-0755

25

Vemurafenib, selective BRAF inhibitor versus LY3009210, pan-RAF inhibitor

• Vemurafenib is a potent BRAF inhibitor while LY3009120 also inhibits
ARAF and RAF1

• Vemurafenib is only efficacious in cells driven by V600E BRAF while
LY3009120 is efficacious in both V600E BRAF cells, as well as in cells driven by activating RAS mutants

  • Vemurafenib
  • LY3009120

26

Profiling Vemurafenib pathway effects in A375 (V600E BRAF), HCT116 (G13D K-RAS), and PC3 (WT RAF, WT RAS) cells, 48 hours

MS Signal ratio [(Treated)/(Control)]

V600E BRAF
G13D KRAS
WT

• Target engagement observed in both sensitive and resistant cells

Direct

targets

• Pathway effects predominantly observed in sensitive cells (V600E BRAF)

Pathway effects

• Hyper phosphorylation of
MEK and ERK in RAS- driven cells may result in HCT116 cells being less sensitive to Vemurafenib than PC3

27

Profiling LY3009120 pathway effects in A375

(V600E BRAF), HCT116 (G13D K-RAS), and PC3 (WT RAF, WT RAS) cells, 48 hours

MS Signal ratio [(Treated)/(Control)]

  • V600E BRAF G13D KRAS
  • WT

• Similar to Vemurafenib,

LY3009120 binds RAF

kinases in sensitive

Direct targets

and resistant cells
• In contrast to

Similar

pathway effects

Vemurafenib, pathways

effects are observed in

both V600E BRAF and G13D KRAS driven cell lines

Different

pathway

effects

28

Profiling the Aurora kinase inhibitor Alisertib – G2/M arrest

MS Signal ratio [(Treated)/(Control)]

PLK1, CDK9, ROCK, FAM20B

Direct targets

EphR

1 hour 24 hours 48 hours

Aurora

Pathway effects

Kinases

• Aurora kinase inhibitors induce G2/M arrest in contrast to CDK and RAF inhibitors which induce G0/G1 arrest

• PLK1 is downregulated during G0/G1 arrest, but upregulated at G2/M arrest

29

Acyl phosphate GTP probe modifies GTPases at a conserved lysine in the phosphate binding loop (P site)

GTP probe

Phosphate

binding loop

Lysine residue

30

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    ISSN 0001-5555 ActaDV Volume 100 2020 Theme issue ADVANCES IN DERMATOLOGY AND VENEREOLOGY A Non-profit International Journal for Interdisciplinary Skin Research, Clinical and Experimental Dermatology and Sexually Transmitted Diseases Frontiers in Dermatology and Venereology - A series of theme issues in relation to the 100-year anniversary of ActaDV Official Journal of - European Society for Dermatology and Psychiatry Affiliated with - The International Forum for the Study of Itch Immediate Open Access Acta Dermato-Venereologica www.medicaljournals.se/adv ACTA DERMATO-VENEREOLOGICA The journal was founded in 1920 by Professor Johan Almkvist. Since 1969 ownership has been vested in the Society for Publication of Acta Dermato-Venereologica, a non-profit organization. Since 2006 the journal is published online, independently without a commercial publisher. (For further information please see the journal’s website https://www. medicaljournals.se/acta) ActaDV is a journal for clinical and experimental research in the field of dermatology and venereology and publishes high- quality papers in English dealing with new observations on basic dermatological and venereological research, as well as clinical investigations. Each volume also features a number of review articles in special areas, as well as Correspondence to the Editor to stimulate debate. New books are also reviewed. The journal has rapid publication times. Editor-in-Chief: Olle Larkö, MD, PhD, Gothenburg Former Editors: Johan Almkvist 1920–1935 Deputy Editors: Sven Hellerström 1935–1969
  • New Century Health Policy Changes April 2021

    New Century Health Policy Changes April 2021

    Policy # Drug(s) Type of Change Brief Description of Policy Change new Pepaxto (melphalan flufenamide) n/a n/a new Fotivda (tivozanib) n/a n/a new Cosela (trilaciclib) n/a n/a Add inclusion criteria: NSCLC UM ONC_1089 Libtayo (cemiplimab‐rwlc) Negative change 2.Libtayo (cemiplimab) may be used as montherapy in members with locally advanced, recurrent/metastatic NSCLC, with PD‐L1 ≥ 50%, negative for actionable molecular markers (ALK, EGFR, or ROS‐1) Add inclusion criteria: a.As a part of primary/de�ni�ve/cura�ve‐intent concurrent chemo radia�on (Erbitux + Radia�on) as a single agent for members with a UM ONC_1133 Erbitux (Cetuximab) Positive change contraindication and/or intolerance to cisplatin use OR B.Head and Neck Cancers ‐ For recurrent/metasta�c disease as a single agent, or in combination with chemotherapy. Add inclusion criteria: UM ONC_1133 Erbitux (Cetuximab) Negative change NOTE: Erbitux (cetuximab) + Braftovi (encorafenib) is NCH preferred L1 pathway for second‐line or subsequent therapy in the metastatic setting, for BRAFV600E positive colorectal cancer.. Add inclusion criteria: B.HER‐2 Posi�ve Breast Cancer i.Note #1: For adjuvant (post‐opera�ve) use in members who did not receive neoadjuvant therapy/received neoadjuvant therapy and did not have any residual disease in the breast and/or axillary lymph nodes, Perjeta (pertuzumab) use is restricted to node positive stage II and III disease only. ii.Note #2: Perjeta (pertuzumab) use in the neoadjuvant (pre‐opera�ve) se�ng requires radiographic (e.g., breast MRI, CT) and/or pathologic confirmation of ipsilateral (same side) axillary nodal involvement.