Pic Of The Day

Posted by rob on October 28, 2004 under Uncategorized | Be the First to Comment

 

A man looks at Spanish painter Pablo Picasso’s “Woman in a Hat” at the museum Palazzo Ruspoli in Rome as part of an exhibit called “Picasso and His Epoch.”

Recent developments in the discovery of protein kinase inhibitors from the urea class.

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Curr Opin Drug Discov Devel. 2004 Sep; 7(5): 600-16
Dumas J, Smith RA, Lowinger TB

With two compounds on the market (Gleevec and Iressa), and a number of drug candidates in late-stage clinical trials, small-molecule kinase inhibitors hold great potential as novel therapies for cancer and inflammatory disorders. Inhibitors from the urea class were first reported in 1996 and have emerged as an important compound class for medicinal chemists due to their unique binding mode and kinase inhibition profile. Currently, five members of this class are undergoing clinical trials, BIRB-796 (Boehringer Ingelheim Pharmaceuticals Inc), BAY-43-9006 (Bayer AG/Onyx Pharmaceuticals Inc), CP-547632 (Pfizer Inc), MLN-518 (Millennium Pharmaceuticals Inc) and KRN-951 (Kirin Brewery Co Ltd). This review focuses on the most recent developments in the discovery of urea-based protein kinase inhibitors.

http://www.hubmed.org/display.cgi?issn=13676733&uids=15503863

[Therapy of chronic myelogenous leukemia in 2004]

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Dtsch Med Wochenschr. 2004 Oct 1; 129(40): 2122-7
Hochhaus A, Berger U, Hehlmann R

Chronic myelogenous leukemia constitutes a clinical model for other neoplastic diseases. The cytogenetic hallmark of CML, the Ph chromosome with the molecular juxtaposition of BCR and ABL genes and the multistep pathogenesis with the stable chronic phase, the accelerated phase and the terminal blast crisis provide the background for the translation of molecular-cytogenetic findings into clinical practice. The systematic development of the selective BCR-ABL inhibitor imatinib was based on the discovery of the molecular pathogenesis of CML. Promising preclinical data were confirmed in phase I-III trials. Concerning hematologic and cytogenetic response and adverse effects imatinib is superior to interferon alpha. Open questions are treatment duration in patients with good response, long term side effects, persistence of minimal residual disease in almost all patients, development of resistance after long term therapy, and the efficacy of combination treatments. Prospective clinical trials, e. g. CML study IV of the German CML Study Group, should answer these questions. The impact of the various treatment modalities (imatinib, interferon alpha, ara-C, allogeneic stem cell transplantation) will be elucidated. The recruitment of newly diagnosed CML patients into CML-study IV is recommended.

http://www.hubmed.org/display.cgi?issn=00120472&uids=15455305

[Complete remission of an idiopathic hypereosinophilic syndrome while using imatinib]

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Dtsch Med Wochenschr. 2004 Oct 1; 129(40): 2104-6
Wolf D, Gastl G, Rumpold H

HISTORY AND ADMISSION FINDINGS: A 47-year-old man with a hypereosinophilic syndrome (HES), which has been known for 20 years, was admitted to our department due to insufficient therapeutic response to hydroxyurea. In general, the patient felt well, but reported increasing neurological problems, such as ataxia, memory deficits and dysarthria. INVESTIGATIONS: Bone marrow assessments corroborated the diagnosis of a HES. However, we were not able to detect the insertional deletion 4q12 with concomitant fusion of the FIP1L1 to the PDGFRA locus. Magnetic resonance imaging (MRI) indicated a granulomatous vasculitis, which was most likely due to the hematologic malignancy. TREATMENT AND COURSE:: Despite negativity for the FIP1L1-PDGFRA fusion gene, therapy was started with the tyrosine kinase inhibitor Imatinib. This led to a rapid normalization of eosinophilic granulocytes in the peripheral blood as well as in the bone marrow. In addition, the neurologic symptoms substantially improved. CONCLUSION: Imatinib provides a potent therapeutic option in FIP1L1-PDGFRA negative patients suffering from HES.

http://www.hubmed.org/display.cgi?issn=00120472&uids=15455302

[An alternative Abl-kinase inhibitor overcomes imatinib resistance mutations of Bcr-Abl oncogenes]

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Dtsch Med Wochenschr. 2004 Oct 1; 129(40): 2100-3
Von Bubnoff N, Peschel C, Duyster J

BACKGROUND AND OBJECTIVE: The tyrosinkinase inhibitor Imatinib is active in Philadelphia-positive (Ph+) leukemia. Mutations within the Bcr-Abl kinase domain represent the major cause for clinical resistance toward imatinib. We aimed to examine, whether the alternative Abl Kinaseinhibitor SKI-DV 2 – 43 may be capable of suppressing the growth of cells expressing mutant forms of Bcr-Abl. METHODS: The proliferation of cells expressing wild-type and mutant forms of Bcr-Abl was measured in the presence of imatinib or the pyrido-pyrimidine SKI-DV 2 – 43. RESULTS: The growth of a cell line expressing wild-type Bcr-Abl was suppressed with higher potency in the presence of SKI-DV 2 – 43 when compared to imatinib. Moreover, SKI-DV 2 – 43 effectively suppressed mutant forms of Bcr-Abl that cause imatinib resistance in patients. CONCLUSION: Therefore, alternative Abl kinase inhibitors might play an important role in the future therapy of Philadelphia-positive leukemias.

http://www.hubmed.org/display.cgi?issn=00120472&uids=15455301

Sole BCR-ABL inhibition is insufficient to eliminate all myeloproliferative disorder cell populations.

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Proc Natl Acad Sci U S A. 2004 10 25;
Wong S, McLaughlin J, Cheng D, Zhang C, Shokat KM, Witte ON

Protein kinase inhibitors can be effective in treating selected cancers, but most suppress several kinases. Imatinib mesylate has been useful in the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia and B cell acute lymphoblastic leukemia through the inhibition of BCR-ABL tyrosine kinase activity. Imatinib mesylate has also been shown to inhibit KIT, ARG, and platelet-derived growth factor receptors alpha and beta, and potentially other tyrosine kinases. We have produced a mutant allele of BCR-ABL (T315A) that is uniquely inhibitable by the small molecule 4-amino-1-tert-butyl-3-(1-naphthyl)pyrazolo[3,4-D]pyrimidine and used it to demonstrate that sole suppression of BCR-ABL activity was insufficient to eliminate BCR-ABL(+) KIT(+)-expressing immature murine myeloid leukemic cells. In contrast, imatinib mesylate effectively eliminated BCR-ABL(+) KIT(+)-expressing leukemic cells. In the cellular context of mature myeloid cells and Pro/Pre B cells that do not express KIT, monospecific BCR-ABL inhibition was quantitatively as effective as imatinib mesylate in suppressing cell growth and inducing apoptosis. These results suggest that the therapeutic effectiveness of small molecule drugs such as imatinib mesylate could be due to the inhibitor’s ability to suppress protein kinases in addition to the dominant target.

http://www.hubmed.org/display.cgi?issn=00278424&uids=15505216

Structural insights into the conformational selectivity of STI-571 and related kinase inhibitors

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Curr Opin Drug Discov Devel. 2004 Sep; 7(5): 639-48
Mol CD, Fabbro D, Hosfield DJ

STI-571 (Gleevec) is a highly successful cancer drug due to its activity as an inhibitor of the Abelson cytoplasmic tyrosine kinase (Abl), which is constitutively active in a majority of patients with chronic myelogenous leukemia. STI-571 also inhibits two type III receptor tyrosine kinases, c-Kit and platelet-derived growth factor receptor, and functions by targeting inactive conformations of these kinases. This review focuses on recent developments in X-ray co-crystal structure analyses of STI-571 bound to Abl and the c-Kit receptor tyrosine kinase domain, and also three other relevant kinase inhibitor co-crystal structures. The similar structural features of these inactive kinases suggest they will be useful for the successful drug discovery and development of specific and targeted gene-based cancer drugs.

http://www.hubmed.org/display.cgi?issn=13676733&uids=15503866

Short interfering RNA (siRNA) targeting the Lyn kinase induces apoptosis in primary, and drug-resistant, BCR-ABL1(+) leukemia cells.

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Nat Med. 2004 10 24;
Ptasznik A, Nakata Y, Kalota A, Emerson SG, Gewirtz AM

We studied the effects of Lyn ablation on the survival of drug-resistant chronic myelogenous leukemia (CML) blast crisis cells using siRNA. Lyn siRNA reduced Lyn protein in both normal hematopoietic cells and BCR-ABL1-expressing (BCR-ABL1(+)) blasts by 80-95%. Within 48 h, siRNA-treated BCR-ABL1(+) blasts underwent apoptosis, whereas normal cells remained viable. This increased dependence on Lyn signaling for BCR-ABL1(+) blast survival provides the basis for rational treatment of drug-resistant CML blast crisis, particularly when lymphoid in nature.

http://www.hubmed.org/display.cgi?issn=10788956&uids=15502840

A phase I and pharmacodynamic study of fludarabine, carboplatin, and topotecan in patients with relapsed, refractory, or high-risk acute leukemia.

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Clin Cancer Res. 2004 Oct 15; 10(20): 6830-9
Cooper BW, Veal GJ, Radivoyevitch T, Tilby MJ, Meyerson HJ, Lazarus HM, Koc ON, Creger RJ, Pearson G, Nowell GM, Gosky D, Ingalls ST, Hoppel CL, Gerson SL

PURPOSE: A novel regimen designed to maximize antileukemia activity of carboplatin through inhibiting repair of platinum-DNA adducts was conducted in poor prognosis, acute leukemia patients. EXPERIMENTAL DESIGN: Patients received fludarabine (10 to 15 mg/m(2) x 5 days), carboplatin (area under the curve 10 to 12 by continuous infusion over 5 days), followed by escalated doses of topotecan infused over 72 hours (fludarabine, carboplatin, topotecan regimen). Twenty-eight patients had acute myelogenous leukemia (7 untreated secondary acute myelogenous leukemia, 11 in first relapse, and 10 in second relapse or refractory), 1 patient had refractory/relapsed acute lymphoblastic leukemia, and 2 patients had untreated chronic myelogenous leukemia blast crisis. Six patients had failed an autologous stem cell transplant. Patients ranged from 19 to 76 (median 54) years. Measurement of platinum-DNA adducts were done in serial bone marrow specimens. RESULTS: Fifteen of 31 patients achieved bone marrow aplasia. Clinical responses included 2 complete response, 4 complete response with persistent thrombocytopenia, and 2 partial response. Prolonged myelosuppression was observed with median time to blood neutrophils >/=200/microl of 28 (0 to 43) days and time to platelets >/=20,000/microl (untransfused) of 40 (24 to 120) days. Grade 3 or greater infections occurred in all of the patients, and there were 2 infection-related deaths. The nonhematologic toxicity profile was acceptable. Five patients subsequently received allografts without early transplant-related mortality. Maximum tolerated dose of fludarabine, carboplatin, topotecan regimen was fludarabine 15 mg/m(2) x 5, carboplatin area under the curve 12, and topotecan 2.55 mg/m(2) over 72 hours. An increase in bone marrow, platinum-DNA adduct formation between the end of carboplatin infusion and 48 hours after the infusion correlated with bone marrow response. CONCLUSIONS: Fludarabine, carboplatin, topotecan regimen is a promising treatment based on potential pharmacodynamic interactions, which merits additional study in poor prognosis, acute leukemia patients.

http://www.hubmed.org/display.cgi?issn=10780432&uids=15501959

Urea derivatives of STI571 as inhibitors of Bcr-Abl and PDGFR kinases.

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Bioorg Med Chem Lett. 2004 Dec 6; 14(23): 5793-7
Manley PW, Breitenstein W, Brüggen J, Cowan-Jacob SW, Furet P, Mestan J, Meyer T

The constitutively active Abl kinase activity of the Bcr-Abl oncoprotein is causative for chronic myelogenous leukemia. Urea derivatives, structurally related to the therapeutic agent STI571, have been identified, which potently inhibit the tyrosine kinase activity of recombinant Abl. In particular a dimethylamino-aniline derivative (18) inhibited c-Abl transphosphorylation with an IC(50) value of 56nM. Although this activity was not translated into cellular activity against the constitutively activated oncogenic Bcr-Abl, a number of compounds from this series potently inhibited cellular PDGFR autophosphorylation. It was also possible to differentiate between c-Abl and PDGFR kinase inhibition, with compound 22 being selective towards Abl and 23 selective for PDGFR.

http://www.hubmed.org/display.cgi?issn=0960894X&uids=15501042