Anti-cancer drug design最新文献

We have previously reported that novobiocin potentiates the cytotoxic activity of etoposide (VP-16) and teniposide (VM-26) in a number of experimental tumor cell lines by inhibition of the efflux of the epipodophyllotoxins by an ATP-requiring transporter. In leukemia cells from 12/19 patients and in ovarian carcinoma cells from 2/4 patients, novobiocin, in a concentration range of 150-1000 microM, increased the intracellular accumulation of VP-16 by 30-250% by inhibiting its efflux. Novobiocin did not significantly increase the intracellular concentration of VP-16 in human mononuclear bone marrow cells from two individuals with normal bone marrow, suggesting that it might be possible to selectively modulate the intracellular accumulation of the epipodophyllotoxin in tumor cells relative to normal hematopoietic tissue. Previous findings from our laboratory have provided evidence that the membrane transporter for VP-16 which is inhibited by novobiocin is distinct from the P-glycoprotein. The expression of MRP, measured by immunoblotting, was variable in novobiocin-responsive and non-responsive leukemia cells, indicating that no direct relationship existed between the modulatory activity of novobiocin on the transport of VP-16 and the expression of the MRP gene. The findings indicate that the novobiocin-sensitive VP-16 transporter is (i) present in high frequency in leukemia and ovarian carcinoma cells, and (ii) probably not the P-glycoprotein or MRP.

The staurosporine derivative PKC412 was originally identified as an inhibitor of protein kinase C (PKC) and subsequently shown to inhibit other kinases including the kinase insert domain receptor (KDR) (vascular endothelial growth factor receptor, VEGF-R2), the receptor of platelet-derived growth factor, and the receptor for the stem cell factor, c-kit. PKC412 showed a broad antiproliferative activity against various tumor and normal cell lines in vitro, and was able to reverse the Pgp-mediated multidrug resistance of tumor cells in vitro. Exposure of cells to PKC412 resulted in a dose-dependent increase in the G2/M phase of the cell cycle concomitant with increased polyploidy, apoptosis and enhanced sensitivity to ionizing radiation. PKC412 displayed a potent antitumor activity as single agent and was able to potentiate the antitumor activity of some of the clinically used cytotoxins (Taxol and doxorubicin) in vivo. The combined treatment of PKC412 with loco-regional ionizing irradiation showed significant antitumor activity against tumors which are resistant to both ionizing radiation and chemotherapeutic agents (dysfunctional p53). The finding that PKC412 is an inhibitor of the VEGF-mediated cellular signaling via inhibition of KDR and PKC in vitro is consistent with the in vivo inhibition of VEGF-dependent angiogenesis in a growth factor implant model. Orally administered PKC412 also strongly inhibited retinal neovascularization as well as laser-induced choroidal neovascularization in murine models. In summary, PKC412 may suppress tumor growth by inhibiting tumor angiogenesis in addition to directly-inhibiting tumor cell proliferation via its effects on PKC and/or other protein kinases. PKC412 is currently in Phase I clinical trials for treatment of advanced cancer as well as for the treatment of ischemic retinopathy.

Angiogenesis, or the sprouting of new blood vessels, is a central process in the growth of solid tumors. For many cancers, the extent of vascularization of a tumor is a negative prognostic indicator signifying aggressive disease and increased potential for metastasis. Recent efforts to understand the molecular basis of tumor-associated angiogenesis have identified several potential therapeutic targets, including the receptor tyrosine kinases for the angiogenic factor vascular endothelial growth factor (VEGF). Here we review the approach taken at SUGEN, Inc. to discover and develop small molecule inhibitors of receptor tyrosine kinases as anti-angiogenic agents. We focus on SU5416, a selective inhibitor of VEGF receptors that is currently in clinical development for the treatment of advanced malignancies. Its biochemical, biological and pharmacological properties are reviewed and clinical implications discussed.

A congeneric series of paullones were characterized using a 3-D QSAR with cyclin-dependent kinase 1 (CDK1) inhibition data. A homology model of CDK1-cyclin B was developed from the crystal structure of CDK2-cyclin A, which subsequently served as the basis for the structure-based design. Paullones were docked into the ATP binding site of the CDK1-cylin B models and were optimized with molecular mechanics. Hydropathic analyses of the paullone-CDK1 complexes were performed after the atom types were assigned based on each ligand's electronic properties calculated from quantum mechanics. Hydropathic descriptors formed a significant multiple regression equation that predicts paullone IC50 data. The results indicate that the combination of hydropathic descriptors with molecular mechanics geometries are sufficient to design overt steric and chemical complementarity of the ligands. However, the electronic properties derived from quantum mechanics helped direct synthetic chemistry efforts to produce ligands that promote better charge transfer and strengthen hydrogen bonding as facilitated by resonance stabilization. Compounds with low affinity for CDK1 were poor charge acceptors and made less than ideal hydrogen bonding arrangements with the receptor. These considerations led to the prediction that structures such as 9-cyanopaullone would be considerably more potent than the parent compound, a finding supported by enzyme inhibition data. Also, 9-nitropaullone emerged as a paullone which also had similar potency in enzyme inhibition as well as a favorable anti-proliferative activity profile in living cells.

The erbB family of tyrosine kinases represents a versatile set of four plasma membrane receptors that possesses enormous diversity in signaling capability. The rationale to target this receptor system as an approach to cancer chemotherapy has continued to become more compelling with time. Both preclinical and clinical data strongly support the involvement of these receptors in the formation and progression of human cancers as well as establish a high correlation in cancer patients between receptor/ligand expression and poor prognosis. During the past 4 years significant progress has been made in the area of epidermal growth factor receptor tyrosine kinase inhibitors and new structural classes have emerged that exhibit enormous improvements with regard to potency, specificity, and in vitro and in vivo efficacy. More recent advancements in this field have resulted in the discovery of very specific, irreversible inhibitors of the erbB family that provide unique pharmacological properties and exceptional efficacy. The in vivo performance of these modern kinase inhibitors has improved to the point where several compounds are either in clinical trials or very near to that point in their development. This article will provide a brief biological review of the erbB family and the justification for targeting this receptor family in cancer therapeutics, and then highlight some of the more promising kinase antagonists with emphasis on irreversible inhibitors.

The insulin-like growth factor-1 receptor (IGF-1R) has been shown to be of critical importance for tumor development and tumor cell survival of various types of malignancies. We have previously demonstrated that an adequate N-linked glycosylation of IGF-1R is required for its translocation to the cell surface in melanoma cells. This raises the possibility of using glycosylation inhibitors as therapeutic agents against IGF-1R-dependent malignancies. In this study we show that inhibition of N-linked glycosylation using tunicamycin or the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor lovastatin resulted in down-regulation of IGF-1R at the cell surface in Ewing's sarcoma cell lines (RD-ES and ES-1 cells). The down-regulation of plasma membrane-bound IGF-1R was correlated with a drastic decrease in IGF-1R autophosphorylation, suggesting biochemical inactivation of the receptor. Whereas RD-ES and ES-1 cells responded differently with regard to DNA synthesis, the decrease in IGF-1R expression was accompanied by a rapid and substantial decrease in survival of both cell lines. Our data suggest that relatively untoxic HMG-CoA reductase inhibitors (e.g. lovastatin) could have therapeutic significance in IGF-1R-dependent neoplasms like Ewing's sarcoma.

UCN-01 (7-hydroxystaurosporine) is a protein kinase inhibitor which is under development as an anti-cancer agent in the USA and Japan. Although UCN-01 was originally isolated from the culture broth of Streptomyces sp. as a protein kinase C-selective inhibitor, its ultimate target as an anti-cancer agent remains elusive. As a single agent, UCN-01 exhibits two key biochemical effects, namely accumulation of cells in the G1 phase of the cell cycle and induction of apoptosis. Both these effects may be important for its anti-cancer activity. As a modulator, UCN-01 enhances the cytotoxicity of other anti-cancer drugs such as DNA-damaging agents and anti-metabolite drugs through putative abrogation of G2 and/or S phase accumulation induced by these anti-cancer agents. Currently, in addition to UCN-01, four other indolocarbazole anti-cancer drugs-two protein kinase inhibitors, CGP 41251, CEP-751, and two DNA-damaging agents, NB-506 and a Rebeccamycin analog-are undergoing clinical investigations in the USA, Europe or Japan. In this review, we would like to address the differences and similarities of these indolocarbazole compounds as anti-cancer agents with regard to their mechanism(s) of action, the effects on cell cycle progression, induction of apoptosis and modulation of drug sensitivity.

The structure of alphabeta-tubulin was refined and used in the docking study for taxuspine D, paclitaxel and their analogues. The conformational space in the binding site was explored by molecular dynamics. The interaction energy was calculated by minimization in the active site of beta-tubulin. The C-5 cinnamoyl side chain in taxuspine D is found to mimic the C-13 side chain of paclitaxel. A virtual taxane with a new C-5 side chain is predicted to be more active than taxuspine D. The C-13 side chain could be replaced with a novel C-5 side chain if the conformation of the core skeleton is modified.

The tertiary amine N-oxide (nitracrine-N-oxide, 1b) of the 1-nitroacridine nitracrine is a bis-bioreductive agent showing very high hypoxic selectivity (approximately 1000-fold) against tumour cells in culture, but only modest activity against the hypoxic subfraction of tumours in vivo. Because the hypoxic selectivity of 1b was considered to depend significantly on the rate of enzyme-mediated reduction of the N-oxide group, this paper reports the preparation and evaluation of a series of analogues in which the environment of this group was modified. Three analogues contained more weakly basic N-oxides, while two others had varying degrees of steric bulk around the N-oxide. In all but one case (an aromatic N-oxide), the N-oxides were much less cytotoxic (10- to 300-fold) than the corresponding tertiary amines towards AA8 Chinese hamster cells under aerobic conditions. Both the N-oxides and the corresponding amines were more cytotoxic to an ERCC-1 mutant defective in nucleotide excision repair, indicating that DNA alkylation was the cytotoxic event. However, there was no apparent correlation of these parameters with structure. All of the aliphatic N-oxides, with the exception of the aromatic N-oxide example, showed substantial (70- to 800-fold) hypoxic selectivity against AA8 cells in a clonogenic assay. While the weakly basic derivatives were the least selective, there was no apparent relationship between hypoxic selectivity and the steric environment of the N-oxide. Selectivity for hypoxic cells in culture is shown to depend on the hypoxic selectivity of the corresponding tertiary amine (reflecting O2-inhibitable reduction of the 1-nitro group) and the differential in aerobic toxicity between amine and N-oxide (a measure of the potential toxicity increase achievable by reducing the N-oxide). Four analogues whose structures fairly represented the range of steric and electronic modifications of the N-oxide site were evaluated against the hypoxic subfraction of cells in KHT tumours in vivo, but were inactive. These results suggest that either such modifications do not exert significant effects on N-oxide reduction, or that the rate of such reduction is not a factor limiting the in vivo activity of the parent analogue 1b.