Chapter 4
Discovery and Development of Third-Generation Platinum Antitumor Agents with Oral Activity 1,2
2
Downloaded by UNIV OF CALIFORNIA SAN DIEGO on August 31, 2015 | http://pubs.acs.org Publication Date: August 25, 2005 | doi: 10.1021/bk-2005-0903.ch004
Christen M. Giandomenico and Ernest Wong 1
2
778 Elm Avenue, Blaine, WA 98230 AnorMED Inc., 20353 64 Avenue, #200, Langley, British Columbia V2Y 1N5, Canada th
The drug discovery process is illustrated by describing the collaborative process that was used to identify three potential platinum anti-tumor compounds (JM216 (satraplatin), AMD473 and JM335) and ultimately select two for clinical development. The selection cascade and medicinal chemistry program and selection criteria that lead to the identification of these preclinical candidate compounds is described. The additional preclinical studies and chemical development activities required to qualify these compounds as preclinical leads and ultimately as clinical candidates is described.
30
© 2005 American Chemical Society
In Medicinal Inorganic Chemistry; Sessler, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005.
Downloaded by UNIV OF CALIFORNIA SAN DIEGO on August 31, 2015 | http://pubs.acs.org Publication Date: August 25, 2005 | doi: 10.1021/bk-2005-0903.ch004
31 Cisplatin and carboplatin are widely used anti-cancer agents because they are effective against a broad range of cancers including testicular, ovarian, bladder, head and neck, and non-small cell lung cancer. A third platinum compound, oxaliplatin, was approved in 2002 for the treatment of colorectal cancer. Unfortunately, many initially responsive tumors develop resistance to these agents and each have serious toxicities such as nephrotoxicity, nausea and vomiting, ototoxicity, peripheral neuropathy, and myelosuppression that significantly degrade patient quality of life. A new platinum agent that successfully addresses these unmet needs would find utility in chemotherapy. The question facing the drug discovery scientist is how to devise a program that has a reasonable probability of identifying a developable platinum compound. There are a variety of possible approaches to this problem. This article will illustrate the drug discovery process that was used to identify three potential platinum anti-tumor compounds and ultimately select two for clinical development. Some of the early stage development requirements will also be discussed. AnorMED and its predecessor, the Johnson Matthey Biomedical group undertook a project to discover and develop new platinum antitumor agents, in collaboration with the Institute of Cancer Research. This program prepared and evaluated a large number of platinum compounds and ultimately identified three distinct classes of platinum compound having development potential. The final preclinical lead from each of these classes is depicted in Figure 1. The orally
?
A c
