PARP-1 Inhibitors In Oncology
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PARP-1 inhibitors have shown promise in oncology by potentiating the effects of DNA damaging chemotherapy agents. Cephalon identified a pyrrolocarbazole hit that inhibited PARP-1 but had poor properties. Through structure-based design and SAR studies, they developed CEP-8983, a potent PARP inhibitor. A prodrug, CEP-9722, was synthesized to improve solubility and pharmacokinetics. In preclinical studies, CEP-8983 and its active metabolite CEP-9397 potentiated the effects of temozolomide in tumor cell lines. CEP-9722 advanced to Phase 1 and 2 clinical trials for evaluation as monotherapy and
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PARP-1 Inhibitors In Oncology
- 1. PARP-1 Inhibitors in Oncology The Discovery and Development of CEP-9722, an Orally Active Prodrug for the Treatment of Cancer
- 4. Role of PARP-1 in DNA Repair N C N C A. de Murcia & M. de Murcia (1994) TIBS 19 , 172 DNA Damage ADP-ribose PARP Activation NAD + ATP
- 5. Role of PARP-1 in DNA Repair N C N C A. de Murcia & M. de Murcia (1994) TIBS 19 , 172 DNA Damage ADP-ribose PARP Activation NAD + ATP DNA damage repaired
- 6. Role of PARP-1 in DNA Repair N C N C A. de Murcia & M. de Murcia (1994) TIBS 19 , 172 DNA Damage ADP-ribose PARP Activation NAD + ATP DNA damage repaired Healthy cell
- 7. Role of PARP-1 in DNA Repair N C N C A. de Murcia & M. de Murcia (1994) TIBS 19 , 172 PARP Inhibitor DNA damage persists DNA Damage ADP-ribose PARP Activation NAD + ATP Damage repaired, Healthy cell
- 8. Role of PARP-1 in DNA Repair N C N C A. de Murcia & M. de Murcia (1994) TIBS 19 , 172 PARP Inhibitor DNA damage persists DNA Damage ADP-ribose PARP Activation NAD + ATP Damage repaired, Healthy cell Apoptosis, Cell death
- 9. PARP activity, NAD + , and ATP levels are interdependent Ha, H. C.; Neurobiology of Disease 7, 225–239 (2000)
- 12. Earlier Competitor PARP-1 Scaffolds
- 13. o inc. radiation sensitivity of Chinese hamster V79 cells o Radiat Res; 126(3), 367 (1991) o potentiates TMZ and TP growth inhib. in human tumor cell lines o Clin Cancer Res; 6, 2860 (2000 ) Proof of Concept o Clinical trials candidate
- 14. o Potentiates TMZ, Cisplatin, radiation in syngeneic and xenograft tumor models o Clin Cancer Res; 13, 2728 (2007) o Completing Phase 2 trials w/TMZ o Irreversible inhibitor o Excellent Phase 2 results o First PARP inhibitor in Phase 3 trials o Failed primary endpoint o Cancelled Phase 3 trials for breast cancer o Commencing Phase 3 for ovarian cancer o Phase 1 trial for various cancers o Well tolerated o Commencing Phase 2 for Mantle Cell Lymphoma In the Clinic
- 18. Modeling of CEP-3499 with PARP-CF Wells, Bihovsky; BMCL, 16, 1151 (2006)
- 19. PARP Inhibitor Discovery Flow In Vitro Cytotoxicity Assays (PARP inhibitors + Chemotherx.) In Vivo Chemo-Potentiation Studies GBMs /TMZ, HT-29/Irinotecan Significant shift in tumor versus normal cell kill versus chemotherx. alone In Vivo PAR Accumulation Assay No enhanced human myelotoxicity in vitro Biochemical efficacy in vivo Cmpd Scale-Up Significant potentiation of anti-tumor efficacy versus chemotherx. alone; acceptable systemic tolerability. Go/No Go Decision PK and Tolerability in Rodents rh PARP Inhibition Assay PC12 cells/H 2 O 2 insult Assay for Inhibition of NAD+ Depletion In vitro and in vivo evaluation on normal tissues; clinical chemistry and histopathology IC 50 < 50 nM 50% recovery @ < 1 uM > 90% max. recovery Criteria
- 20. General Route to Pyrrolocarbazoles
- 31. General Synthesis of Alkoxy Analogs
- 32. Summary SAR
- 38. 1-Aza-4-Alkoxy Series Synthetic Challenges
- 42. Synthetic Process for Drug Candidate CEP-8983
- 43. Synthetic Process for CEP-8983 (cont.)
- 53. Oncology Candace Burns Jennifer Grobelny Kathryn Hunter Sonya Pritchard Hugh Zhao Susan Jones-Bolin Bruce Ruggeri Acknowledgements Chung Ho Park Dandu Reddy Sankar Chatterjee Ron Bihovsky Gregory Wells Chemistry Mary Birchler Laura Gwinn Jean Husten Bruce Jones Biochemistry Seetha Murthy Damaris Rolon-Steele Kelli Zeigler Lisa Aimone Mark Ator Jim Diebold Ming Tao Derek Dunn Allison Zulli Bob Hudkins Fox Chase Cancer Center Andres Klein-Szanto
- 54. Extra slides
- 55. TMZ – Hydrolysis gives active form Temozolomide is not directly active but undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC). The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA. Alkylation (methylation) occurs mainly at the O 6 and N 7 positions of guanine.
- 56. 29th Annual J.P. Morgan Healthcare Conference January 10-12, 2011 Cephalon Oncology Pipeline
- 58. Wang; Am J Cancer Res; 1(3):301-327 (2011)
- 59. Wang; Am J Cancer Res; 1(3):301-327 (2011)
Editor's Notes
- A small-molecule prodrug of CEP-8983, a novel 4-methoxy-carbazole inhibitor of the nuclear enzymes poly(ADP-ribose) polymerase (PARP) 1 and 2, with potential antineoplastic activity. Upon administration and conversion from CEP-9722, CEP-8983 selectively binds to PARP 1 and 2, preventing repair of damaged DNA via base excision repair (BER). This agent enhances the accumulation of DNA strand breaks and promotes genomic instability and apoptosis. CEP-8983 may potentiate the cytotoxicity of DNA-damaging agents and reverse tumor cell chemo- and radioresistance. PARP catalyzes post-translational ADP-ribosylation of nuclear proteins that signal and recruit other proteins to repair damaged DNA and can be activated by single strand breaks in DNA.
- Inhibitors of PARP-1 have potential therapeutic utility in oncology through potentiation of the anti-tumor activity of radiation or chemotherapeutic DNA damaging agents. Until more recently, the potentiation observed in-vitro and in-vivo could not be unequivocally linked to inhibition of PARP due to limitations with respect to potency, selectivity, toxicity, and deliverability of compounds.
- Poly (ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that catalyzes the synthesis of poly-ADP-ribose chains from NAD+ as part of the DNA repair process.
- Poly (ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that catalyzes the synthesis of poly-ADP-ribose chains from NAD+ as part of the DNA repair process.
- Poly (ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that catalyzes the synthesis of poly-ADP-ribose chains from NAD+ as part of the DNA repair process.
- Poly (ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that catalyzes the synthesis of poly-ADP-ribose chains from NAD+ as part of the DNA repair process.
- Poly (ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that catalyzes the synthesis of poly-ADP-ribose chains from NAD+ as part of the DNA repair process.
- A model of PARP overactivation-mediated cytotoxicity. Reactive oxygen species (ROS) such as nitric oxide (NO z ), superoxide anion (O2--), peroxynitrite (ONOO2), or hydroxyl radical (OH z ) are generated during inflammation or ischemia–reperfusion. These ROS damage cellular molecules like proteins, lipids, and DNA. DNA damage activates PARP , synthesizing poly(ADP-ribose) polymer from its substrate b-nicotinamide adenine dinucleotide (NAD1). Limited amounts of DNA damage can be repaired by cellular DNA repair enzymes, and PARP, in this case, acts as a sensor for DNA damage, modulating the repair process. In apoptotic cell death, activated caspases cleave PARP protein to inhibit a futile DNA repair process and preserve cellular ATP, which is essential for the apoptotic process. Extensive DNA damage can lead to overactivation of PARP . With excessive activation of PARP, NAD1 is depleted, and in efforts to resynthesize NAD1, ATP is also depleted. Hence, necrotic cell death involves energy loss. Depletion of ATP can transform an ongoing apoptotic process into necrosis with intracellular ATP levels regulating the mode of cell death.
- - Colorectal Carcinoma with Irinotecan #2 choice HNSCC with radiotherapy #3 choice
- More recent competition?
- Screening of Cephalon’s internal library identified pyrrolocarbazole CEP-3498 as a potent inhibitor of PARP-1 with an IC50 value of 35 nM, although with poor cellular permeability and solubility. The chemistry objective was to improve the enzyme and cell potency, and the physical-chemical properties to allow either oral or i.v. delivery in the clinic.
- Key H-bond interactions between imide C=O and N-H groups with backbone N-H and C=O of Gly863 ; H-bond between indole-NH and C=O of Glu988 side-chain; aromatic pi-stacking of aryl rings of Tyr896 and Tyr907 with B and D rings of the carbazole, resp.; cyclopentyl ring fits closely into fold formed by Lys861 side-chain, Ala898, Trp861, and Asn987; open pocket around 3- and 4-positions of the inhibitor provided opportunity for SAR development.
- Key H-bond interactions between lactam C=O and N-H groups with backbone N-H and C=O of Gly863 ; H-bond between indole-NH and C=O of Glu988 side-chain; aromatic pi-stacking of aryl rings of Tyr896 and Tyr907 with B and D rings of the carbazole, resp.; cyclopentyl ring fits closely into fold formed by Lys861 side-chain, Ala898, Trp861, and Asn987; open pocket around 3- and 4-positions of the inhibitor provided opportunity for SAR development.
- But with limited opportunity elsewhere on the core template, the aryl group was retained for further SAR development.
- 1-Aza analog CEP-9397 modeled with PARP-1 active site, postulated as more potent due to an additional H-bond between the 1-aza group and the amine side chain of Met890.
- Need reference!