Jürg Zimmermann

Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells

The bcr–abl oncogene, present in 95% of patients with chronic myelogenous leukemia (CML), has been implicated as the cause of this disease. A compound, designed to inhibit the Abl protein tyrosine kinase, was evaluated for its effects on cells containing the Bcr–Abl fusion protein. Cellular proliferation and tumor formation by Bcr–Abl–expressing cells were specifically inhibited by this compound. In colony–forming assays of peripheral blood or bone marrow from patients with CML, there was a 92–98% decrease in the number of bcr–abl colonies formed but no inhibition of normal colony formation. This compound may be useful in the treatment of bcr–abl–positive leukemias.

Protein kinases as targets for anticancer agents: from inhibitors to useful drugs

Many components of mitogenic signaling pathways in normal and neoplastic cells have been identified, including the large family of protein kinases, which function as components of signal transduction pathways, playing a central role in diverse biological processes, such as control of cell growth, metabolism, differentiation, and apoptosis. The development of selective protein kinase inhibitors that can block or modulate diseases caused by abnormalities in these signaling pathways is widely considered a promising approach for drug development. Because of their deregulation in human cancers, protein kinases, such as Bcr-Abl, those in the epidermal growth factor-receptor (HER) family, the cell cycle regulating kinases such as the cyclin-dependent kinases, as well as the vascular endothelial growth factor-receptor kinases involved in the neo-vascularization of tumors, are among the protein kinases considered as prime targets for the development of selective inhibitors. These drug-discovery efforts have generated inhibitors and low-molecular weight therapeutics directed against the ATP-binding site of various protein kinases that are in various stages of development (up to Phase II/III clinical trials). Three examples of inhibitors of protein kinases are reviewed, including low-molecular weight compounds targeting the cell cycle kinases; a potent and selective inhibitor of the HER1/HER2 receptor tyrosine kinase, the pyrollopyrimidine PKI166; and the 2-phenyl-aminopyrimidine STI571 (Glivec(R), Gleevec) a targeted drug therapy directed toward Bcr-Abl, the key player in chronic leukemia (CML). Some members of the HER family of receptor tyrosine kinases, in particular HER1 and HER2, have been found to be overexpressed in a variety of human tumors, suggesting that inhibition of HER signaling would be a viable antiproliferative strategy. The pyrrolo-pyrimidine PKI166 was developed as an HER1/HER2 inhibitor with potent in vitro antiproliferative and in vivo antitumor activity. Based upon its clear association with disease, the Bcr-Abl tyrosine kinase in CML represents the ideal target to validate the clinical utility of protein kinase inhibitors as therapeutic agents. In a preclinical model, STI571 (Glivec(R), Gleevec) showed potent in vitro and in vivo antitumor activity that was selective for Abl, c-Kit, and the platelet-derived growth factor-receptor. Phase I/II studies demonstrated that STI571 is well tolerated, and that it showed promising hematological and cytogenetic responses in CML and clinical responses in the c-Kit-driven gastrointestinal tumors.

Potent and selective inhibitors of the Abl-kinase : Phenylamino-pyrimidine (PAP) derivatives

Abstract Due to its relatively clear etiology, Chronic myelogenous leukemia (CML) represents an ideal disease target for a therapy using a selective inhibitor of the Bcr-Abl tyrosine protein kinase. Extensive optimization of the class of phenylamino-pyrimidines yielded highly potent and selective Bcr-Abl kinase inhibitors. Compound 1 shows high potency (IC50 = 38 nM) and selectivity for the Abl tyrosine protein kinase at the in vitro level.

Imatinib: a selective tyrosine kinase inhibitor

The understanding of the pathophysiology of a large number of cancer types provides a strategy to target cancer cells with minimal effect on normal cells. Protein phosphorylation and dephosphorylation play a pivotal role in intracellular signaling; to regulate signal transduction pathways, there are approximately 700 protein kinases and 100 protein phosphatases encoded within the human genome. In cancer, as well as in other proliferative diseases, unregulated cell proliferation, differentiation and survival frequently results from abnormal protein phosphorylation. Although it is often possible to identify a single kinase that plays a pivotal role in a given disease, the development of drugs based upon protein kinase inhibition has been hampered by unacceptable side effects resulting from a lack of target selectivity. With the growing understanding of the molecular biology of protein tyrosine kinases and the use of structural information, the design of potential drugs directed towards the bind adenosine triphosphate (ATP)-binding site of a single target has become possible. These advances have transferred emphasis away from the identification of potent kinase inhibitors and more towards issues of target selectivity, cellular efficacy, therapeutic effectiveness and tolerability. In this paper, the relationship between molecular biology and drug discovery methods, as utilized for the identification of anticancer drugs, will be illustrated.

PHENYLAMINO-PYRIMIDINE (PAP)-DERIVATIVES : A NEW CLASS OF POTENT AND HIGHLY SELECTIVE PDGF-RECEPTOR AUTOPHOSPHORYLATION INHIBITORS

Abstract Phenylamino-pyrimidines represent a novel class of inhibitors of the PDGF-receptor autophosphorylation with a high degree of selectivity versus other tyrosine and serine/threonine kinases. Optimum activity of ca 10 nM (IC50) was observed when the phenylamino-group which is attached to the pyrimidine carries a benzamide-moiety with a lipophilic substituent in 4-position.

Design, synthesis and investigation of mechanisms of action of novel protein kinase C inhibitors: perylenequinonoid pigments

A series of perylenequinonoid pigments (PQPs) and related compounds were synthesized and screened for the inhibition of protein kinase C (PKC), a key enzyme involved in cellular differentiation and proliferation, and a potential target for anticancer and antiviral chemotherapeutic drugs. This study has established PQPs as efficient PKC inhibitors, and elucidated aspects of the light-enhanced action mode of the PKC inhibitors. Comparative studies between natural and synthetic PQPs led to the recognition of the effect of certain structural features of PQPs on PKC inhibition, including the skeleton of the 3,10-dihydroxy-4,9-perylenequinonoid chromophore and the configuration of the two side chains at positions 1 and 12. Calphostin C was identified as a superior PKC inhibitor of the POP class, and with the latter as a representative structure, we investigated the mechanism of PKC inhibition by PQPs via electron paramagnetic resonance spectroscopy in conjunction with the spin-trapping technique, absorption and fluorescence spectroscopy, photochemical and photobiological studies, and enzyme methodology. Multiple modes of action are suggested for PKC inhibition, comprising the following steps: (1) the binding of PQPs to the PKC regulatory domain via complexation; (2) the photobonding between mercapto groups of PKC cysteine residues and the PQP quinonoid moiety; and (3) the PQP-sensitized photodamage of PKC via Type I and/or Type II photosensitization.

The preparation of polymer bound β-ketoesters and their conversion into an array of oxazoles

A series of diverse polymer bound β-ketoesters have been prepared using a transesterification reaction between t-butyl β-ketoesters and a hydroxybutyl functionalized JandaJel resin. Additionally, these highly useful polymer bound substrates have also been prepared using a transesterification reaction with commercially available methyl or ethyl β-ketoesters using lithium perchlorate as a catalyst. The polymer bound β-ketoesters were then converted into the corresponding α-diazo-β-ketoesters using standard diazo transfer conditions and these products were utilized in the synthesis of an array of oxazoles.

A New Structural Class of Selective and Non-covalent Inhibitors of the Chymotrypsin-like Activity of the 20S Proteasome

We describe the identification and in vitro characterization of a series of 2-aminobenzylstatine derivatives that inhibit non-covalently the chymotrypsin-like activity of the 20S proteasome. Our initial SAR data demonstrate that the 2-aminobenzylstatine core structure can effectively serve as the basis for designing potent, selective and non-covalent inhibitors of the chymotrypsin-like activity of the 20S proteasome.

Protein kinase C-α inhibitors; structure-activity relationships in bis-indole series

Abstract To assess the role of the amine and ester containing oligopeptide side-chains in bis-indole protein kinase C inhibitors, six novel hybrids in this series were synthesized. These new compounds displayed effective inhibitory activity against protein kinase C-α.

Selective Killing of BCR-ABL Positive Cells with a Specific Inhibitor of the ABL Tyrosine Kinase

Chronic myelogenous leukemia (CML) is a malignancy of the pluripotent hematopoietic stem cell. This disease accounts for 15–20% of all leukemias with an annual incidence of between 1 to 2 cases per 100,000 persons per year. The median age of onset is approximately 50 years of age. Clinically, the disease is characterized by a chronic phase in which the only apparent abnormality is the massive expansion of functionally normal myeloid lineage cells 1. During this chronic phase, myeloid cells retain the capacity to differentiate normally. Following an average chronic phase duration of about three years, the disease transforms to an accelerated or blast phase in which there is a progressive loss of the capacity for terminal differentiation of myeloid lineage cells along with the accumulation of cytogenetic abnormalities 1.