Sunday, July 3, 2016

Olaparib | PARP Inhibitor | Poly (ADP-ribose) Polymerase Inhibitor | Treatment for BRCA-mutated Ovarian Cancer

Olaparib [4-(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)phthalazin-1(2H)-one] is an oral, small molecule, poly (ADP-ribose) polymerase (PARP) inhibitor developed for the treatment of solid tumours, including breast cancer gene (BRCA) mutation positive ovarian cancer [1, 2].

Olaparib: 2D and 3D Structure

Olaparib is a potent first-in-class oral PARP-1 inhibitor that preferentially kills cancer cells by exploiting DNA repair pathway deficiencies. This mode of action allows for activity in a range of tumor types harboring DNA repair deficiencies, inducing synthetic lethality in BRCA1/2-deficient tumor cells. 

In December 2014, the capsule formulation of Olaparib, was approved in the EU and USA for the treatment of BRCA-mutated ovarian cancer.

Epithelial Ovarian Cancer and PARP Inhibitors
Epithelial ovarian cancer (OC) remains the leading cause of death from gynecological malignancies. The incidence of developing OC significantly increases in carriers of germline mutations, mainly in either breast cancer gene 1 (BRCA1) or 2 (BRCA2) genes. These genes are implicated in 10 -15% of all OC cases, including those in women without a family history of breast or OCs.
Patients with mutations in the BRCA1 and/or BRCA2 gene; consequently have tumours that lack the homologous recombination (HR) pathway involved in error-free repair of DNA double-strand breaks (DSBs).
The PARP family consists of 17 nuclear proteins with enzymatic and scaffolding properties and DNA repair protein recruiting capability. The best understood member, PARP-1 is a key component of the base excision repair system that is responsible for repairing DNA single strand breaks (SSB). This is crucial to correcting DNA endogenous base damage induced by radiation and alkylating agents.
PARP-1 leads to persistent DNA SSB which when encountered by the replication forks, are converted into DNA double strand breaks (DSB). PARP inhibitors (PARPi) trap the PARPenzymes at damaged DNA and trapped PARP-DNA complexes are cytotoxic. Normal cells, proficient in homologous recombination repair (HRR), are able to repair DSB and survive under conditions of PARP inhibition. Cancer cells harboring BRCA or other mutations in DNA repair genes are defective in HRR, and consequently, susceptible to the synthetic lethality via PARPi.
PARP inhibitors (PARPi) exploit synthetic lethality to target DNA repair defects in hereditary OC. Synthetic lethality is based on the concept that loss of function in both genes leads to cell death, whereas loss of function in either of these genes alone permits survival.

Olaparib as PARP Inhibitor
Optimization of a series of 4-benzyl-2H-phthalazin-1-ones inhibitors of PARP leads to the identification of Olaparib. The selectivity profile of Olaparib is typical of the inhibitors tested in this class. As expected from the close homology between PARP-1 and PARP-2, Olaparib is essentially equipotent against the two PARP isoforms (IC50 PARP-1, PARP-2 = 5, 1 nM), whereas it is 300 times less effective against the inhibition of tankyrase (IC50 = 1.5 uM) [3].
Moreover, Olaparib demonstrated exciting clinical efficacy as a monotherapy in BRCA1- and BRCA2- deficient ovarian and breast cancers trials.

Dosages and Approvals
Olaparib (Tradename: Lynparza) is approved (since December 2014) as a capsule formulation of Olaparib, in the EU and USA for the treatment of BRCA-mutated ovarian cancer. The approved dosage is 400 mg twice daily. A tablet formulation is in global phase III trials (including in the USA, EU, Australia, Brazil, Canada, China, Israel, Japan, Russia and South Korea).

KuDOS Pharmaceuticals is credited with the discovery and development of Olaparib. KuDOS had expertise in cancer therapies that exploit inhibition of DNA repair and had Olaparib in phase I trials at the time of acquisition by AstraZeneca. In December 2005, AstraZeneca announced plans to acquire the UK biotechnology company KuDOS Pharmaceuticals Limited.

Common name: AZD 2281; AZD-2281; AZD2281; KU-0059436; KU-59436; Olaparib
Trademarks: Lynparza
Molecular Formula: C24H23FN4O3
CAS Registry Number: 763113-22-0
CAS Name: 4-[3-[4-(Cyclopropylcarbonyl)piperazin-1-ylcarbonyl]-4-fluorobenzyl] phthalazin-1(2H)-one
Molecular Weight: 434.47
InChI: InChI=1S/C24H23FN4O3/c25-20-8-5-15(14-21-17-3-1-2-4-18(17)22(30)27-26-21)13-19(20)24(32)29-11-9-28(10-12-29)23(31)16-6-7-16/h1-5,8,13,16H,6-7,9-12,14H2,(H,27,30)
Mechanism of Action: Poly (ADP-ribose) polymerase inhibitor; PARP Inhibitor
Activity: Treatment of BRCA-mutated Ovarian Cancer; Antineoplastics; Antineoplastics Agents
Status: Launched 2014 (US, EU)
Chemical Class: Phthalazines; Amides; Cyclopropanes; Fluorobenzenes; Piperazines; Small-molecules; Fluorine containing
Originator: KuDOS Pharmaceuticals/AstraZeneca

Olaparib Synthesis

WO2008047082: A highly optimized route to Olaparib has been described which requires no chromatographic separations, and allows isolation of the final product in high purity and selectivity as a single crystal form. See also Ref. 3.


1H NMR (Estimated) for Olaparib

Experimental: 1H NMR (DMSO-d6): 12.57 (s, 1H), 8.27 (dd, J = 7.7, 1.2  Hz, 1H), 7.97 (dd, J = 7.7, 1.2 Hz, 1H), 7.94-7.78 (m, 2H),  7.49-7.40 (m, 1H), 7.42-7.34 (m, 1H), 7.24 (t, J = 9.0 Hz, 1H),  4.34 (s, 2H), 3.86-3.10 (m, 8H), 2.09-1.82 (m, 1H), 0.74 (m,  4H).

Sideeffects: Adverse events (AEs) were generally mild or moderate in severity; however, Olaparib (in monotherapy) was associated with a 1.7-fold higher incidence of grade 3 or 4 AEs than placebo.

Adverse events (AEs) reported in 10 % more Olaparib than placebo recipients included nausea, fatigue, vomiting and anaemia; the most common being fatigue and anaemia [1].

1. Deeks, E. D. Olaparib: first global approval. Drugs 2015, 75(2), 231-40. (FMO only)
2. Lheureux, S.; et. al. Olaparib for the treatment of ovarian cancer. Expert Opinion on Orphan Drugs. 2014, 2(5), 497-508. (FMO only)
3. Menear, K. A.; et. al. 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J Med Chem 2008, 51(20), 6581-6591. (FMO only)
4. Menear, K. A.; et. al. Polymorphic form of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2h-phthalazin-1-one. WO2008047082A2