[2002]-[ONT-093]-[oral P-gp inhibitor][Phase 1]
Reversing Multidrug Resistance Reversing Multidrug Resistance During Chemotherapy During Chemotherapy
Approximately 50% of cancer patients receive
chemotherapy, and as many as 75% of these patients
experience intrinsic or acquired resistance to a broad
spectrum of chemotherapeutic agents.
This phenomenon, termed multidrug resistance (MDR), is the most common cause of chemotherapy failure. It is well established that the ajority of tumors develop MDR through over-expression of he drug efflux pump P-glycoprotein (P-gp). Inhibition of Pgp s acknowledged as a viable means of reversing MDR;
however, existing P-gp inhibitors so far have demonstrated
limited clinical success due to limitations in potency and
specificity.
Ontogen (Carlsbad, CA; www.ontogen.com) is currently conducting Phase I clinical studies to evaluate the eversal of MDR using ONT-093, a highly potent, specific and oral P-gp inhibitor. ONT-093 (Fig. 1) was designed with unique structural, biological and metabolic
properties that enable it to prevent the emergence
not capable of successfully crossing the blood brain barrier, such as drugs for treating bacterial infection, cancer, HIV and neurocognitive disorders.
Pre-clinical studies demonstrated that ONT-093 is a
successful inhibitor of P-gp in vitro and reverses MDR in
human tumors in animal models. Four ONT-093 clinical
trials have established the safety of ONT-093 in healthy
volunteers and an additional Phase I study of ONT-093,
initiated in May 2001, is evaluating the tolerability and
pharmacokinetics of ONT-093 combined with intravenous
TaxolTM (paclitaxel) in cancer patients.
Ontogen has filed an IND in Canada, and a U.S. IND filing is pending.
Ontogen also is evaluating ONT-093 in Phase I
clinical testing to enhance the oral bioavailability of drugs that are P-gp substrates requiring either high dosage forms or intravenous administration. P-gp also has been implicated in the poor oral absorption of a significant number of important therapeutic agents, and ONT-093 as an adjuvant agent could significantly enhance the utility of cancer drugs such as Taxol and TaxotereTM (docetaxel).
Ontogen's discovery capabilities are driven by
proprietary, industry-leading technology systems,
of resistance at the onset of chemotherapy and to
reverse resistance that develops during the course
of cancer treatment (Fig. 2). In addition to treating
cancer, ONT-093 has a potential for the inhibition of
P-gp at the blood brain barrier, which would
increase central nervous system (CNS) penetration
of drugs that are P-gp substrates. This approach
would increase the efficacy of existing drugs that are
Figure 1: ONT-93 Structure
OntoBLOCKTM and OntoCHROM®, which enable the
company and its partners to significantly enhance drug
discovery accuracy and efficiency and alleviate traditional
bottlenecks in the drug discovery process. These systems
improve upon conventional methods of key research
processes, including rapid synthesis of large compound
libraries and high-throughput purification, which may
dramatically lower R&D expenditures.
OntoBLOCKTM allows organic chemists to efficiently
synthesize libraries of 5,000 to 50,000 compounds at the
exceptional rate of 1,000 compounds per day. This proven
technology, coupled with sustained efforts to conduct highthroughput biological screening (HTS) for candidate
compounds, has resulted in a drug discovery and
optimization process that is significantly faster than
traditional methods.
OntoCHROM® is a supercritical fluid chromatography
(SFC) system that uses supercritical CO2 as the
mobile phase and UV-triggered, mass-directed fraction
collection. OntoCHROM® allows for practical highthroughput
semi-preparative purification of chemical
libraries (250 compounds every 8 hours), at up to 100%
purity, with minimal solvent waste. OntoCHROM®'s fully
automated, four-channel system allows simultaneous
purification of four 96-well plates, with direct well-to-well mapping of the desired product positively identified by mass spectrometry) in the target plate.
Using these technologies Ontogen has created a library exceeding 200,000 compounds. Some other targets which Ontogen is creating compounds against include: IGF-1 receptor tyrosine kinase, an effector in breast and prostate cancer, as well as psoriasis; SHP-2 tyrosine phosphatase, an enzyme critical to the growth of EGF-dependent tumors; c-Met tyrosine kinase, an effector in colorectal cancer; and focal adhesion kinase (FAK), a
suppressor of apoptosis in various tumor types. Ontogen was founded in July 1992 by Dr. Barry E. Toyonaga, with investment from Allen & Co., Johnson & Johnson, Lombard Odier Immunology Fund, N.V. Organon, Novo Nordisk A/S, and Sequoia Capital.
Ontogen also has had collaborations with Amgen, Boehringer Ingelhiem, Novo Nordisk A/S and Nippon Organon K.K.
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