Tyrosine kinase inhibitors: From rational design to clinical trials

Abstract

Protein kinases play a crucial role in signal transduction as well as in cellular proliferation, differentiation, and various regulatory mechanisms. The inhibition of growth related kinases, especially tyrosine kinases, might provide new therapies for diseases such as cancer. The progress made in the crystallization of protein kinases has confirmed that the ATP-binding domain of tyrosine kinases is an attractive target for drug design. Three successful examples of drug design at Novartis using a tyrosine kinase as a molecular target are described. PKI166, a pyrrolo[2,3,-d]pyrimidine derivative, is a dual inhibitor of both the EGFR and the ErbB2 kinases. The compound entered clinical trials in 1999, based on its favorable preclinical profile: potent inhibition of EGF-mediated signalling in cells, in vivo antitumor activity in several EGFR overexpressing xenograft tumor models in nude mice, long-lasting inhibition of EGF-stimulated EGFR autophosphorylation in tumor tissue, good oral bioavailability in animals, and no prohibitive in vitro and in vivo toxicity findings. The anilino-phthalazine derivative PTK787/ZK222584 (Phase I, co-developed by Schering AG, Berlin) is a potent and selective inhibitor of both the KDR and Flt-1 kinases with interesting anti-angiogenic and pharmacokinetic properties (orally bioavailable). STI571 (Glivec, Gleevec), a phenylamino-pyrimidine derivative, is a potent inhibitor of the Abl tyrosine kinase, which is present in 95% of patients with chronic myelogenous leukemia (CML). The compound specifically inhibits proliferation of v-Abl and Bcr-Abl expressing cells (including cells from CML patients) and shows anti-tumor activity as a single agent in animal models at well-tolerated doses. Pharmacologically relevant concentrations are achieved in the plasma of animals (oral administration). Promising data from phase I and II clinical trials in CML patients (98% haematological response rate in Phase I) support the fact that the STI571 represents a new treatment modality for CML. In addition, potent inhibition of the PDGFR and c-Kit tyrosine kinases also indicates its possible clinical use in solid tumors.

Dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition of breast cancer cells

“…While used to target EGFR phosphorylation, PKI166 also inhibits phosphorylation of HER2 (Traxler et al, 2001). In this study the high HER2-expressing SKBR3 cell line was one of the more sensitive to growth inhibition and apoptosis induced by PKI166.…”

“…In the present study we have used PKI166 {4-(R)-phenethylamino-6-(hydroxy)phenyl-7H-pyrrolo[2,3-d]-pyrimidine}, an inhibitor of the pyrrolopyrimidine class that has been shown to inhibit the intracellular domain of the EGF-R kinases with an IC 50 of 0.7 nM, with less activity against other tyrosine kinases (Traxler et al, 2001). The goals of the present study were to characterise the pattern of expression of activated ERK1/2 in established breast cancer cell lines and determine whether this correlates with EGFR or HER2 status.…”

Pre-B Cell Receptor Assesses the Quality of IgH Chains and Tunes the Pre-B Cell Repertoire by Delivering Differential Signals

“…Indeed, when 38B9 cells that were uninfected or infected with empty vector (mock) were cultured for 24 or 48 h in the presence of 0.1 M STI571 (33), an inhibitor of Abl, more than half the cells showed apoptosis as defined by the presence of subdiploid DNA, compared with Ͻ2% of cells cultured in the absence of the reagent (Fig. 2, A and B, not all data shown).…”

Qsar in-Silico Method Analysis of Antitumoral Acridones as a Anticancerous Agent and Dipiperidines as Ccr2 Antagonists

“…In recent years great progress has been made in the treatment of cancer, and so the life expectation of patients with cancer has been improved remarkably emerging science within the past decade has created many opportunities for fundamentally new approaches to tackle this disease . [1] Nearly all cancers are caused by abnormalities in the compound through a screening technique to identify those that help fight cancer while leaving healthy cells unharmed. Therefore efforts were directed to develop anti-cancerous agents containing quinolones and dipiperidines rings.…”