The invention provides novel derivatives of CCI-779 formed using a unique enzymatic process.
Rapamycin 42-ester with 2,2-bis(hydroxymethyl)propionic acid (CCI-779) is an ester derivative of rapamycin which has demonstrated significant inhibitory effects on tumor growth in both in vitro and in vivo models.
CCI-779 may delay the time to progression of tumors or time to tumor recurrence which is more typical of cytostatic rather than cytotoxic agents. CCI-779 is considered to have a mechanism of action that is similar to that of sirolimus. CCI-779 binds to and forms a complex with the cytoplasmic protein FKBP, which inhibits an enzyme, mTOR (mammalian target of rapamycin, also known as FKBP12-rapamycin associated protein [FRAP]). Inhibition of mTOR's kinase activity inhibits a variety of signal transduction pathways, including cytokine-stimulated cell proliferation, translation of mRNAs for several key proteins that regulate the G1 phase of the cell cycle, and IL-2-induced transcription, leading to inhibition of progression of the cell cycle from G1 to S. The mechanism of action of CCI-779 that results in the G1-S phase block is novel for an anticancer drug.
In vitro, CCI-779 has been shown to inhibit the growth of a number of histologically diverse tumor cells. Central nervous system (CNS) cancer, leukemia (T-cell), breast cancer, prostate cancer, and melanoma lines were among the most sensitive to CCI-779. The compound arrested cells in the G1 phase of the cell cycle.
In vivo studies in nude mice have demonstrated that CCI-779 has activity against human tumor xenografts of diverse histological types. Gliomas were particularly sensitive to CCI-779 and the compound was active in an orthotopic glioma model in nude mice. Growth factor (platelet-derived)-induced stimulation of a human glioblastoma cell line in vitro was markedly suppressed by CCI-779. The growth of several human pancreatic tumors in nude mice as well as one of two breast cancer lines studied in vivo also was inhibited by CCI-779.
A great deal of effort has been put on the preparation of its new derivatives to explore the structure-activity. However, due to the presence of multiple functional groups, rapamycin is very susceptible to acidic and basic reaction conditions. Therefore, selective structural modification is difficult. Modification of rapamycin has mainly focused on the 42-hydroxy position as its ether and ester products (for example: CCI-779), and 7-position derivatives. Few products other than 7, and 42-position modifications have been reported.