Preparation and Evaluation of Heterocyle-Containing Piperazinediones as Antitumor Agents

Thirty pyridinylpiperazinediones synthesized as tyrosine kinase inhibitors exhibited profound inhibitory activities against 60 human-disease oriented cancer cell lines (IC50 10-7 to 10-8 M, NCI, USA), with activities higher than taxol against drug-resistant breast, renal and cololectal cancers. The lead compound, TW01, not only increased the life span but also inhibited tumor growth of mice bearing human hepatoma, non-small cell lung cancer and breast cancer. Anti-angiogenesis was also confirmed as part of the mode of action. Most importantly, TW01 exhibited wide therapeutic window with high inhibitory activity on tumor-related protein kinases while with minimal activity on 136 receptors, transporters and enzymes in the toxicity panel screening. Technical transfer to AngioRx Co. was executed in 2003, which lead to the consequent application for IPR protection in 19 countries. However, only compounds with pyridinyl-piperazinediones core structure were granted for patent protection. We are thus facing challenges from big pharma, as they can easily prepare me-too piperazinediones with their full capacity to bypass our IPR, unless we have broader IPR coverage before the therapeutic implication of TW01 is disclosed. We believe that line-extention products are necessary for broaden the coverage of IPR protection. Moreover, population-based studies indicated that the use of signal transduction-related agents leads to a reduction in mortality from various cancers (aspirin, Celecoxib, Erbitux, YC-1 etc). Moreover, signal transduction-based drugs with anti-angiogenesis effect demonstrated anti-inflammatory and immunomodulating (IMiDs) properties (thalidomide and lenalidomide, IMiDs) per se or as immunomodulators in combination with cytotoxic agents. As TW01 analogues showed profound activity against certain tyrosine kinases along the signal transduction, it is rational to conduct inventory screening and seek for new indications as NSAIDs, anti-pletelet aggregation agents or as immunomodulating agents. , We therefore propose a three year project to conduct studies in the following aspects: (1) to synthesize heterocycle substituted piperazinediones as line extention products; (2) to evaluate antitumor and anti-angiogenesis activities; (3) to evaluate potential anti-inflammatory, immunomodulating activities and anti-pletelet aggregation activities for patent coverage of new indications; (4) to seek for molecular targets by system-based research (SBR) of proteomics or DNA microarray; (5) to synthesize patentable biotin-spacer-piperazinedione ligands for use in avidin-immobilized affinity column chromatography for the purification of proteins; (6) to establish the interactive chemistry-preformulation-PD-PK feed-back operation model for fast PD/PK optimization. The anticipated results will be (1) the generation of more than 200 patentable new molecular entities as line-extension antitumor agents for patent coverage; (2) as drug candidates or, when necessary, as substitute for TW01; (2) the generation of patentable new molecular entities with new indication on anti-inflammatory, immunomodulation and anti-pletelet aggregation; (4) the generation of patentable ligands for use in immobilized affinity columns for the purification of target proteins.

Project ID:PD9508-0577
External Project ID:NSC95-2323-B182-001