Andrew Fant University Of North Carolina Eshelman School Of Pharmacy
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Design of Kinase Inhibitors with Polypharmacological Modes of Action Andrew Fant University of North Carolina Eshelman School of Pharmacy Division of Medicinal Chemistry and Natural Products
9 September 2009 Apsel, B. et. al. Targeted Polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat. Chem. Biol. 2008, 4, 691-699
Cancer in the United States • 23.1% of US Deaths in 2006 (cdc.gov) • Second-leading cause in USA • “War On Cancer” since Nixon in 1971 • Full $50M for NC Cancer Hospital & Linneberger Center • However, not a single disease…
http://msnbc.msn.com/id/c3783216
Hallmarks of Malignancy
Hannahan & Weinberg Cell 1000:57
Autonomy in Growth Signals
Herbst,R.S et.al. Lung Cancer NEJM 2008, 359, 13 1367-1380
Phosphoinositides are Major Second Messengers • • • • •
EGFR TrkA Family IGR CAM Kinases RAS
• Indirectly regulated by PTEN • Feed AKT and mTOR Image courtesy of Sigma-Aldrich
mTOR as a Nexus
Tseng, et al. Drug Discovery Today 12:112
Why Block TOR in particular?
Shmelze & Hall Cell 103:253
Kinases as Targets • Pro – Primary Regulatory Mechanism in vivo – They can selectively recognize each other – The ATP binding site takes a small molecule
• Con – Too Crucial for Life Processes – Specificity in proteinprotein interactions – You really want to create an ATPmimetic inhibitor?
Approved First-Generation Kinase Inhibitors N HN
F
N
N
O
HN N
HN O
N
Cl N
O
gefitinib
N
imatininb
O N
O N H N H O
F N H O O
O
N N
O
erlotinib
N
HN
N N
H N Cl
OH N
S O
dasatinib
N
N
sunitinib
Potential For Overlap? H N
O
N HN
N
N
Bcr-Abl & c-Kit
HN O
N
N O
N
multi-protein kinase & PI3 Kinases
O
N
HN
OH O OH
O O
O HO
O
O H O
O
PI3 Kinase & PLK1
O
Apsel, et. al. Nat.Chem. Bio. 4:691
OH OH
O
A Very Distant Relationship
Apsel, et. al. Nat.Chem. Bio.
Invitrogen High-Throughput Kinase Assay
http://www.invitrogen.com/site/us/en/home/Products-and-Services/Applications/Drug-Discovery/Target-and-Lead-Identification-and-Validation/KinaseBiology/Kinase-Activity-Assays/Adapta-Universal-Kinase-Assay.html
Hits OH NH2
NH2
N
N N
N
S1
Apsel, et. al. Nat.Chem. Bio. 4:691
N
N N
N
S2
Profile
Apsel, et. al. Nat.Chem. Bio. 4:691
SAR for Pyrazolopyrimidine Scaffold exocyclic amine must be able to donate to a hydrogen bond
NH2 N
R1 N
N
N R2
R1= naphthyl derivatives favored, distal substituents OK, especially with H-bond recipients; N in ring helps. don’t come too far off the sides of rings R2= methyl or isopropyl acceptable, t-butyl kills activity. 4 or 5 member ring works, especially with heteroatom. Sterochemistry insensitive NH2 N
N N
op. cit.: supplementary materials
N
O
P3O103-
OH OH
Into the Pocket S1
S2
. Apsel, et. al. Nat.Chem. Bio. 4:691
Conserved Binding Mode
RCSB entry 3ene
Structural Basis for Selectivity
Apsel, et. al. Nat.Chem. Bio. 4:691
Structural Selectivity Redux
Billanges, et. al. Nat. Chem. Bio. 4 648
PP121 with PI3K and mTOR
O
HN N
N
NH2
O
N
N
N
N N
N
Apsel, et. al. Nat.Chem. Bio. 4:691
N
OH
PP121 with Src and Ret
HN N
O O
NH2
N
N
O
N N
N
N H
N
N N
OH
N H O
F N H
Apsel, et. al. Nat.Chem. Bio. 4:691
N
PP121 Overcomes Mutational Resistance HN N NH2 N
N N
N
N HN
N
N
HN O
N N
O N O
N
N N
OH
Apsel, et. al. Nat.Chem. Bio. 4:691
Conclusions • Kinase Inhibitors aren’t as selective as once thought • It is possible to screen libraries of known Kinase Inhibitors for secondary binding properties • Proper targeting of polypharmacology allows mutational resistance to be avoided • These techniques do depend on a common endogenous ligand. Your mileage may vary.
Acknowledgements • • • • •
Alex Tropsha Mike Jarstfer Adrienne Cox Tropsha Lab Warren DeLano/Pymol
9 September 2009 Apsel, B. et. al. Targeted Polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat. Chem. Biol. 2008, 4, 691-699
Cancer in the United States • 23.1% of US Deaths in 2006 (cdc.gov) • Second-leading cause in USA • “War On Cancer” since Nixon in 1971 • Full $50M for NC Cancer Hospital & Linneberger Center • However, not a single disease…
http://msnbc.msn.com/id/c3783216
Hallmarks of Malignancy
Hannahan & Weinberg Cell 1000:57
Autonomy in Growth Signals
Herbst,R.S et.al. Lung Cancer NEJM 2008, 359, 13 1367-1380
Phosphoinositides are Major Second Messengers • • • • •
EGFR TrkA Family IGR CAM Kinases RAS
• Indirectly regulated by PTEN • Feed AKT and mTOR Image courtesy of Sigma-Aldrich
mTOR as a Nexus
Tseng, et al. Drug Discovery Today 12:112
Why Block TOR in particular?
Shmelze & Hall Cell 103:253
Kinases as Targets • Pro – Primary Regulatory Mechanism in vivo – They can selectively recognize each other – The ATP binding site takes a small molecule
• Con – Too Crucial for Life Processes – Specificity in proteinprotein interactions – You really want to create an ATPmimetic inhibitor?
Approved First-Generation Kinase Inhibitors N HN
F
N
N
O
HN N
HN O
N
Cl N
O
gefitinib
N
imatininb
O N
O N H N H O
F N H O O
O
N N
O
erlotinib
N
HN
N N
H N Cl
OH N
S O
dasatinib
N
N
sunitinib
Potential For Overlap? H N
O
N HN
N
N
Bcr-Abl & c-Kit
HN O
N
N O
N
multi-protein kinase & PI3 Kinases
O
N
HN
OH O OH
O O
O HO
O
O H O
O
PI3 Kinase & PLK1
O
Apsel, et. al. Nat.Chem. Bio. 4:691
OH OH
O
A Very Distant Relationship
Apsel, et. al. Nat.Chem. Bio.
Invitrogen High-Throughput Kinase Assay
http://www.invitrogen.com/site/us/en/home/Products-and-Services/Applications/Drug-Discovery/Target-and-Lead-Identification-and-Validation/KinaseBiology/Kinase-Activity-Assays/Adapta-Universal-Kinase-Assay.html
Hits OH NH2
NH2
N
N N
N
S1
Apsel, et. al. Nat.Chem. Bio. 4:691
N
N N
N
S2
Profile
Apsel, et. al. Nat.Chem. Bio. 4:691
SAR for Pyrazolopyrimidine Scaffold exocyclic amine must be able to donate to a hydrogen bond
NH2 N
R1 N
N
N R2
R1= naphthyl derivatives favored, distal substituents OK, especially with H-bond recipients; N in ring helps. don’t come too far off the sides of rings R2= methyl or isopropyl acceptable, t-butyl kills activity. 4 or 5 member ring works, especially with heteroatom. Sterochemistry insensitive NH2 N
N N
op. cit.: supplementary materials
N
O
P3O103-
OH OH
Into the Pocket S1
S2
. Apsel, et. al. Nat.Chem. Bio. 4:691
Conserved Binding Mode
RCSB entry 3ene
Structural Basis for Selectivity
Apsel, et. al. Nat.Chem. Bio. 4:691
Structural Selectivity Redux
Billanges, et. al. Nat. Chem. Bio. 4 648
PP121 with PI3K and mTOR
O
HN N
N
NH2
O
N
N
N
N N
N
Apsel, et. al. Nat.Chem. Bio. 4:691
N
OH
PP121 with Src and Ret
HN N
O O
NH2
N
N
O
N N
N
N H
N
N N
OH
N H O
F N H
Apsel, et. al. Nat.Chem. Bio. 4:691
N
PP121 Overcomes Mutational Resistance HN N NH2 N
N N
N
N HN
N
N
HN O
N N
O N O
N
N N
OH
Apsel, et. al. Nat.Chem. Bio. 4:691
Conclusions • Kinase Inhibitors aren’t as selective as once thought • It is possible to screen libraries of known Kinase Inhibitors for secondary binding properties • Proper targeting of polypharmacology allows mutational resistance to be avoided • These techniques do depend on a common endogenous ligand. Your mileage may vary.
Acknowledgements • • • • •
Alex Tropsha Mike Jarstfer Adrienne Cox Tropsha Lab Warren DeLano/Pymol
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