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Bioorganic and Medicinal Chemistry Letters
Volumn 18, Issue 12, 2008, Pages 3551-3555
TrkA kinase inhibitors from a library of modified and isosteric Staurosporine aglycone
Author keywords

Kinase inhibitor; Modified K 252a aglycone; TrkA
Indexed keywords

ACETALDEHYDE; AGLYCONE; ALCOHOL; CARBAMIC ACID; CARBAMIC ACID DERIVATIVE; CARBAZOLE DERIVATIVE; CARBON; EPOXIDE; HYDROXYL GROUP; HYDROXYMETHYL 7 OXO INDENOPYRROLOCARBAZOLE DERIVATIVE; INDENE DERIVATIVE; INDOLE; INDOLOCARBAZOLE; KETONE; LESTAURTINIB; NITROGEN; PROTEIN TYROSINE KINASE A; PROTEIN TYROSINE KINASE INHIBITOR; STAUROSPORINE;
EID: 44849120199     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.05.012     Document Type: Article
Times cited : (20)
References (37)
  • 21
    • 44849091074 scopus 로고
    • For a discussion in the lack of selectivity see
    • For a discussion in the lack of selectivity see. Tamaoki T., and Nomoto H. Biochemistry 8 (1990) 732
    • (1990) Biochemistry , vol.8 , pp. 732
    • Tamaoki, T.1    Nomoto, H.2
  • 28
    • 44849113993 scopus 로고    scopus 로고
    • For the design and synthesis of 4a see Hudkins, R. L.; Knight, E. Jr. US Patent 5, 705, 511.
    • For the design and synthesis of 4a see Hudkins, R. L.; Knight, E. Jr. US Patent 5, 705, 511.
  • 31
    • 44849114496 scopus 로고    scopus 로고
    • 2, 0.1% BSA, 2.5% DMSO, and various concentrations of test compound was added to the plate. The reaction was initiated by adding recombinant human TrkA kinase and was allowed to proceed at 37 °C for 15 min. The primary antibody, N1 europium-labeled anti-phosphotyrosine (PT66) antibody (Wallac # AD0041), was then added to detect the reaction product (phosphorylated PLC-γ/GST). After 1-h incubation at 37 °C, enhancement solution (Wallac # 1244-105) was added
    • 50 values were calculated by nonlinear regression using the sigmoidal dose-response (variable slope) equation in GraphPad Prism.
  • 32
    • 0034651237 scopus 로고    scopus 로고
    • TrkA intact cell assay: The inhibition of NGF-stimulated phosphorylation of trk was performed as described in 15c. Briefly, subconfluent NIH3T3-TrkA (positive control) and NIH3T3-vector (negative control) cells were treated with test compounds for 1 h at 37 °C. After stimulation with NGF for 5 min, the cells were rinsed with ice-cold PBS, and then lysed with lysis buffer containing 1 mM activated sodium vanadate. Clarified cell lysates corresponding to equal amounts of protein were then immunoprecipitated with anti-trk antibody (CEP-21) for 1 h, followed by incubation with Protein A-Sepharose for another hours at 4 °C. Immunoprecipitates were analyzed on a 7.5% SDS-polyacrylamide gel, and then transferred onto a Millipore PVDF membrane. The membrane was immunoblotted with 4G10 anti-phosphotyrosine antibody, followed by incubation with HRP-coupled goat anti-mouse IgG.
    • Angeles T.S., Lippy J.S., and Yang S.X. Anal. Biochem. 278 (2000) 93 TrkA intact cell assay: The inhibition of NGF-stimulated phosphorylation of trk was performed as described in 15c. Briefly, subconfluent NIH3T3-TrkA (positive control) and NIH3T3-vector (negative control) cells were treated with test compounds for 1 h at 37 °C. After stimulation with NGF for 5 min, the cells were rinsed with ice-cold PBS, and then lysed with lysis buffer containing 1 mM activated sodium vanadate. Clarified cell lysates corresponding to equal amounts of protein were then immunoprecipitated with anti-trk antibody (CEP-21) for 1 h, followed by incubation with Protein A-Sepharose for another hours at 4 °C. Immunoprecipitates were analyzed on a 7.5% SDS-polyacrylamide gel, and then transferred onto a Millipore PVDF membrane. The membrane was immunoblotted with 4G10 anti-phosphotyrosine antibody, followed by incubation with HRP-coupled goat anti-mouse IgG. Phosphorylated bands were visualized by enhanced chemiluminescence. Cell score as measured by a densitometer: 0 = no decrease; 1 = 1-25%; 2 = 26-50%; 3 = 51-75%; 4 = 76-100%
    • (2000) Anal. Biochem. , vol.278 , pp. 93
    • Angeles, T.S.1    Lippy, J.S.2    Yang, S.X.3
  • 33
    • 44849142238 scopus 로고    scopus 로고
    • 50 values (data not shown). With few exceptions (most likely due to cell permeability or solubility), a good correlation was observed between the enzyme and cell activities of the Staurosporine-like molecules described here.
    • 50 values (data not shown). With few exceptions (most likely due to cell permeability or solubility), a good correlation was observed between the enzyme and cell activities of the Staurosporine-like molecules described here.
  • 34
    • 44849113653 scopus 로고    scopus 로고
    • note
    • Since the nature of the substrate controls the pi-facial selectivity for our system, diastereomeric ratios were obtained in the range of ∼1:1 to 85:15. In some cases reversal in facial selectivity were also noticed (see Ref. 14a).
  • 35
    • 20144381281 scopus 로고    scopus 로고
    • It has been shown that the (3′S)-epi-K-252a with an altered orientation of the free hydroxyl group of the sugar is 11-fold more potent for TrkA kinase than K-252a, indicting the importance of the orientation the hydroxyl group toward TrkA kinase activity and selectivity
    • It has been shown that the (3′S)-epi-K-252a with an altered orientation of the free hydroxyl group of the sugar is 11-fold more potent for TrkA kinase than K-252a, indicting the importance of the orientation the hydroxyl group toward TrkA kinase activity and selectivity. Gingrich D.E., Yang S.X., Gessner G.W., Angeles T.S., and Hudkins R.L. J. Med. Chem. 48 (2005) 3776
    • (2005) J. Med. Chem. , vol.48 , pp. 3776
    • Gingrich, D.E.1    Yang, S.X.2    Gessner, G.W.3    Angeles, T.S.4    Hudkins, R.L.5

* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.