Cep7055

3.4.2. Other types of anti-VEGF therapy

Bevacizumab is a recombinant humanized monoclonal IgG1 antibody against all isoforms of VEGF-A, which are ligands of the VEGFR-1 and VEGFR-2. Bevacizu-mab was the first approved agent to inhibit tumor angiogenesis, in 2004 by the FDA and in 2005 in Europe. It is used in combination with other drugs such as 5-fluorouracil or irinotecan for the first-line treatment of patients with metastatic colorectal cancer, and is expected to be approved for other tumors such as NSCLC and renal cell cancer.33 Cytotoxic monoclonal antibodies for related kinases such as PR0-001, an antibody for FGFR-3, are also being developed for the treatment of FGFR-3-expressing myeloma.34

Inhibition of the VEGFR activity can also be accomplished using catalytic RNA molecules known as ribozymes, which down-regulate VEGFR function by specifically cleaving the mRNAs for the primary VEGFRs. Angiozyme35 is one of these ribozymes, which is under clinical studies for the treatment of solid tumors.

3.4.3. Inhibitors of platelet-derived growth factor (PDGF)

Suramin is a polysulphonated naphthylurea originally developed for the treatment of trypanosomiasis and onchocerciasis. Recent studies have shown that suramin possess a variety of biological effects, including anti-AIDS activity due to its capacity to inhibit reverse transcriptase and to prevent HIV entry into the cell. More recently, suramin is also been used in the treatment of cancer and it is being evaluated in clinical trials in combination with several other chemothera-peutic agents in patients with a variety of solid tumors.36 Suramin blocks the activity of several angiogenic factors, especially PDGF and FGF, and is also an inhibitor of heparanase (see Section 2.2.2 of Chapter 10). It is also internalized into the cell where it may affect the activity of various key enzymes involved in the intracellular transduction of mitogenic signals including protein kinase C (PKC).

Suramin

3.5. Inhibitors of FLT-3

FLT-3 is a membrane TK structurally related to PDGFR. Activating mutations of FLT-3 are present in about 30% of acute myeloid leukaemia (AML) patients and are associated with lower cure rates from standard chemotherapy. For this reason, this kinase has become a very popular target for the design of drugs against AML.

Tandutinib37 (MLN-518, CT-53518) is a quinazoline derivative that selectively inhibits FLT-3 and PDGFR and is under clinical trials for AML38 and other cancers. Other FLT-3 inhibitors belong to the indolocarbazole family of compounds because they have been designed as analogues of staurosporine. The most studied compounds of this group are CEP-70139 and PKC-412,40 both of which inhibit several kinases besides FLT-3 and are under clinical evaluation for AML and other tumors.

3.6. Inhibitors of BCR-ABL TK (Abelson kinase)

In normal cells, the bcr and abl genes are in different chromosomes and code different proteins. Chronic myeloid leukaemia (CML) is associated to the exchange of genetic material between the chromosomes 9 and 22, whereby the latter is altered and becomes the so-called Philadelphia chromosome. This transfer leads to a hybrid gene (bcr-abl), formed by transfer of one of the normal genes. This hybrid chromosome harbours the oncogenic protein BCR-ABL, a hybrid PTK with deregulated and high ABL kinase activity, resulting in a high leukocyte count. The TK domain is contained in the ABL portion of the hybrid protein, also known as the Abelson TK, which is therefore the natural target for the design of drugs for the treatment of CML.41

3.6.1. Compounds acting as ATP mimics

Imatinib (STI-571, from 'signal transduction inhibitor') is an inhibitor of BCR-ABL, and the first protein kinase inhibitor to be approved for cancer treatment after a particularly rapid clinical development phase.42 It is effective in about 90% of patients with CML, although resistance is increasingly being encountered.

The lead compounds in the development of imatinib were 2-anilinopyrimidine derivatives 9.1, identified by random screening as inhibitors of PKC, a serine-threonine kinase. All attempts to modify the guanidine portion, shown in bold in Fig. 9.13, were unsuccessful, which was later explained by its involvement in two hydrogen bonds with the active site of kinases. Optimization work led to compound 9.2, bearing a 3-pyridyl substituent, as a potent inhibitor of PKC, and to the discovery that the addition of an amide group to the anilino substituent led to compounds that are dual inhibitors of PKC and ABL, such as 9.3. One potential problem with these compounds is their hydrolysis in vivo to aniline derivatives, which are known to be mutagens. For this reason, the amide moiety had to be optimized for resistance to hydrolysis, and the benzamido group shown in compound 9.4 was chosen for this purpose. In efforts to eliminate the PKC inhibitory activity, a number of analogues were prepared, and it was found that an ortho-methyl substituent led to a selective ABL inhibitor (CGP-53716), which can be explained by assuming that the conformational restriction imposed by this substitution forces the molecule into a conformation that is suitable only for the ABL active site. Finally, further modifications were carried out in order to improve aqueous solubility by the introduction of basic side chains that would allow the preparation of salts, leading to the preparation of STI-571 (imatinib).43 Unexpectedly, it was later shown that the piperazine ring added for this purpose also contributed to binding at the active site (see below). Nilotinib is an imatinib analogue with an imidazole ring replacing the piperidine moiety and a reverse amide function.

X-ray crystallography of a simplified model compound44 and of imatinib itself45 in the active site of ABL and related kinases46 has shown that imatinib binds at the ATP binding site of ABL, showing specificity for an inactive conformation of the kinase. This inactive form contains the N-terminus of the

PKC inhibitor

R and R' optimization

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