TARGETING CELL CYCLE FOR CANCER THERAPY

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TARGETING CELL CYCLE FOR CANCER THERAPY E.
Premkumar Reddy, Ph.D. Fels Institute for Cancer
Research and Molecular Biology
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Cell Cycle in Normal and Tumor Cells
Normal
Tumor
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HUMAN KINOME
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Two Strategies for Kinase Inhibition
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PROPERTIES OF OUR COMPOUND LIBRARY

• Chemistry Library Based on Novel Scaffolds
• Approximately 280 Novel Chemotypes of NCEs
• Expanded by Rational and Iterative Design
• Currently More than 10,000 Molecules Available
• Some Chemotypes Based on Indian Ayurvedic
  Medicine
• Average Molecular Weight 400 (300-900)
• Simple, Scalable and Efficient Synthetic
  Pathways

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NOVEL CHEMOTYPES SYNTHESIZED AT FELS
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Non-ATP Chemotypes of Kinase Inhibitors

• All data based on in vitro or cellular enzyme
  assays
• Novel chemotypes, patentable or filed
• Extensive SAR and lead expansion possibility

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ONCOTOXICITY ASSAY DMSO CONTROL
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ONCOTOXICITY ASSAY ONO1060 (2.5uM)
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STRUCTURE OF ONO1060
Cl
H
SO2
H
F
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ANALOGS OF ONO 1060 AND THEIR ACTIVITY
H
H
NH-CH2COOH
ON 01910
IC 50 0.1mM
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ON 01910 is a Selective Anticancer Agent
Malignant
Non- Malignant
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ON01910 COMPOUNDS BLOCK TUMOR CELL GROWTH AT G2/M
AND NORMAL CELLGROWTH AT G1 PHASE OF CELL CYCLE
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Spindle Effects of ON 01910 in Tumor Cells
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PLK CDK AMPLIFICATION LOOP
CDK1
From a Review by Glover et al. (1998) Genes
Dev. 12, 3777.
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MAPK Array (RD Systems cat ARY002) Z138C cells
treated with 1910 for 6 hrs and the lysate used
for an array experiment.
3 min exposure
1 min exposure
DMSO
10 uM
20 uM
Pp38 MAPK (Thr180/Tyr182)
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Hela cells treated with different concentrations
of ON01910 for 24 hrs
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ON 01910.Na Toxicology Studies

• Maximum Tolerated Single Dose in Rats gt 1200
  mg/m2
• Maximum Tolerated Single Dose in Dogs gt 4000
  mg/m2
• 28 Day Repeat Dosing in Rats
• Five groups of 24 rats (12F, 12M)
• MTD gt 400 mg/m2
• Pharmacokinetics, hematology, chemistry,
  pathology
• 28 Day Repeat Dosing in Dogs
• Five groups of 6 dogs in each (3F, 3M)
• MTD gt1000 mg/m2
• Pharmacokinetics, hematology, chemistry,
  pathology
• Excellent Safety Profile (IND Toxicology)
• No Hemoatological, Nerurological or Liver
  Toxicity Observed

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Human Liver (Bel-7402) Cancer Model
Comparison of 01910.Na and Oxaliplatin (Sanofi)
Dr. Holland, Mt. Sinai
1910 Has Better Activity Alone And Is Curative In
Combination With Oxaliplatin.
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Gemcitabine sensitivity of pancreatic tumor
xenograft cases
Data from Dr. Antonio Jemeno
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Low-density array of fine needle
aspiration-acquired samples
Data from Dr. Antonio Jemeno
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ON01910 overcomes Gemcitabine resistance
Data from Dr. Antonio Jemeno
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ON 01910.Na Phase I Clinical Trial Schedule
Trials Schedule
Hopkins
Cycle I
1
3
5
7
9
11
13
15
17
19
21
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25
27
Days
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ON 01910.Na Side Effects
P
r
o
f
i
l
e

o
f

N
o
v
o
n
e
x
P
r
o
f
i
l
e

o
f

N
o
v
o
n
e
x

• In Pre-clinical Studies
• Thymus and Testes Reduced in Size Upon Daily
  1910 Treatment
• Reversible Effect Reduced in 10 Days, Reversed
  in 28 Days
• No Myelosuppression, No Hepatotoxicity or
  Neurotoxicity
• Irritation of Bile Ducts at High Doses is
  Reversible
• DLT is GI Related
• In Clinical Studies (2h, 24h and 72h Infusion)
• Grade 1 and (1 case) Grade 2 Fatigue
• GI Effects
• No Neutropenia
• No Neurotoxicity
• No Change in Liver Function

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Mt. Sinai Trial Benefit to Advanced Lung Cancer
Patient
Lung Cancer Patient Stable for gt14 Months
gt 10 month survival after failing chemo and
Tarceva
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ON 01910.Na Clinical Trial Summary

• Three Dose Schedules, gt100 Patients 13 Tumor
  Types
• Drug Activity Demonstrated Markers, Stable
  Disease
• Lung, Pancreatic, Colon
• Two Responses with Markers
• Ovarian
• Near Complete Remission
• MDS
• Combination Therapy
• Multiple Chemotherapeutics
• Drug Resistance and other Subtypes
• Toxicity Directly Related to Drug is Limited
• Fatigue and gastrointestinal effects during
  treatment
• No signs of serious hematopoetic or neurological
  toxicity

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ACKNOWLEDGEMENTS
M.V. Ramana Reddy Stephen Cosenza Rick
Mettus Bommi Nathan Ramana Tantravahi Stacey
Baker Ben Hoffman Dr. James Holland (Mt.
Sinai) Dr. Sridhar Mani (Albert Einstein) Dr.
Dan Donehower (Johns Hopkins) Dr. Elaine Sloand
(NIH) Dr. Jerry Groopman (Harvard)