KKB Hot Article: Indirubin derivatives as potent FLT3 inhibitors with anti-proliferative ...

Tue, 20 Apr 2010 19:55:08 +0100

Citation: Indirubin derivatives as potent FLT3 inhibitors with anti-proliferative activity of acute myeloid leukemic cells

Authors: Choi SJ, Moon MJ, Lee SD, Choi SU, Han SY, Kim YC.

PubMed PMID: 20153646

Abstract: Indirubin derivatives were identified as potent FLT3 tyrosine kinase inhibitors with anti-proliferative activity at acute myeloid leukemic cell lines, RS4;11 and MV4;11 which express FLT3-WT and FLT3-ITD mutation, respectively. Among several 5 and 5'-subst...

KKB Hot Article: Phenylaminopyrimidines as inhibitors of Janus kinases (JAKs).

Tue, 20 Apr 2010 19:52:20 +0100

Citation: Phenylaminopyrimidines as inhibitors of Janus kinases (JAKs).

Authors: Burns CJ, Bourke DG, Andrau L, Bu X, Charman SA, Donohue AC, Fantino E, Farrugia M, Feutrill JT, Joffe M, Kling MR, Kurek M, Nero TL, Nguyen T, Palmer JT, Phillips I, Shackleford DM, Sikanyika H, Styles M, Su S, Treutlein H, Zeng J, Wilks AF.

PubMed PMID: 19762238

Abstract: A series of phenylaminopyrimidines has been identified as inhibitors of Janus kinases (JAKs). Development of this i...

KKB Hot Article: 2,4-Diaminopyrimidine MK2 inhibitors. ...

Tue, 20 Apr 2010 19:49:08 +0100

Citation: 2,4-Diaminopyrimidine MK2 inhibitors. Part II: Structure-based inhibitor optimization.

Authors: Harris CM, Ericsson AM, Argiriadi MA, Barberis C, Borhani DW, Burchat A, Calderwood DJ, Cunha GA, Dixon RW, Frank KE, Johnson EF, Kamens J, Kwak S, Li B, Mullen KD, Perron DC, Wang L, Wishart N, Wu X, Zhang X, Zmetra TR, Talanian RV.

PubMed PMID: 19926477

Abstract: We describe structure-based optimization of a series of novel 2,4-diaminopyrimidine MK2 inhibitors....

KKB Hot Article: Substituted 2-arylbenzothiazoles as kinase inhibitors: hit-to-lead optimization.

Tue, 20 Apr 2010 19:46:28 +0100

Citation: Substituted 2-arylbenzothiazoles as kinase inhibitors: hit-to-lead optimization.

Authors: Tasler S, Müller O, Wieber T, Herz T, Pegoraro S, Saeb W, Lang M, Krauss R, Totzke F, Zirrgiebel U, Ehlert JE, Kubbutat MH, Schächtele C.

PubMed PMID: 19692247

Abstract: Based on an (aminoaryl)benzothiazole quinazoline hit structure for kinase inhibition, a systematic optimization program resulted in a lead structure allowing for inhibitory activities in cellular pho...

KKB Hot Article: Targeting cancer with small molecule kinase inhibitors

Tue, 20 Apr 2010 19:43:42 +0100

Citation: Targeting cancer with small molecule kinase inhibitors

Authors: Zhang J, Yang PL, Gray NS.

PubMed PMID: 19104514

Abstract: Deregulation of kinase activity has emerged as a major mechanism by which cancer cells evade normal physiological constraints on growth and survival. To date, 11 kinase inhibitors have received US Food and Drug Administration approval as cancer treatments, and there are considerable efforts to develop selective small molecule inhibitors...

KKB Hot Article: Discovery of 4-morpholino-6-aryl-1H-pyrazolo[3,4-d]pyrimidines as highly ...

Tue, 20 Apr 2010 19:36:09 +0100

Citation: Discovery of 4-morpholino-6-aryl-1H-pyrazolo[3,4-d]pyrimidines as highly potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): optimization of the 6-aryl substituent.

Authors: Verheijen JC, Richard DJ, Curran K, Kaplan J, Lefever M, Nowak P, Malwitz DJ, Brooijmans N, Toral-Barza L, Zhang WG, Lucas J, Hollander I, Ayral-Kaloustian S, Mansour TS, Yu K, Zask A.

PubMed PMID: 19894727

Abstract: Design and synthesis of a ser...

KKB Hot Article: Discovery of pyrimidine benzimidazoles as Src-family selective Lck inhibitors. ...

Tue, 20 Apr 2010 19:33:03 +0100

Citation: Discovery of pyrimidine benzimidazoles as Src-family selective Lck inhibitors. Part II.

Authors: A series of 4-amino-6-benzimidazole-pyrimidines was designed to target lymphocyte-specific tyrosine kinase (Lck), a member of the Src-family kinases (SFKs). These type II inhibitors were optimized using a cellular Lck-dependent proliferation assay and are capable of inhibiting Lck at single-digit nanomolar concentrations. This scaffold is likely to serve a valuable template ...

KKB Hot Article: AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment ...

Tue, 20 Apr 2010 19:26:55 +0100

Citation: AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML).

Authors: Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B, Karaman MW, Pratz KW, Pallares G, Chao Q, Sprankle KG, Patel HK, Levis M, Armstrong RC, James J, Bhagwat SS.

PubMed PMID: 19654408

Abstract: Activating mutations in the receptor tyrosine kinase FLT3 are present in up to approximately 30% of acute myeloid leukemia (AML)...

KKB Hot Article: BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and ...

Tue, 20 Apr 2010 19:14:54 +0100

Citation: BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy

Authors: Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ

PubMed PMID: 18559524

Abstract: Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a novel treatment modality in oncology. Preclinical find...

KKB Hot Article: Selectivity and potency of cyclin-dependent kinase inhibitors

Tue, 20 Apr 2010 19:06:09 +0100

Citation: Selectivity and potency of cyclin-dependent kinase inhibitors

Authors: Sridhar J, Akula N, Pattabiraman N.

PubMed PMID: 16584130

Abstract: Members of the cyclin-dependent kinase (CDK) family play key roles in various cellular processes. There are 11 members of the CDK family known till now. CDKs are activated by forming noncovalent complexes with cyclins such as A-, B-, C-, D- (D1, D2, and D3), and E-type cyclins. Each isozyme of this family is responsible ...

KKB Hot Article: Design, synthesis, and evaluation of indolinones as triple angiokinase ...

Tue, 20 Apr 2010 19:03:32 +0100

Citation: Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120)

Authors: Roth GJ, Heckel A, Colbatzky F, Handschuh S, Kley J, Lehmann-Lintz T, Lotz R, Tontsch-Grunt U, Walter R, Hilberg F

PubMed PMID: 19522465

Abstract: Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a new treat...

KKB Hot Article: Assessing potency of c-Jun N-terminal kinase 3 (JNK3) inhibitors using 2D ...

Tue, 20 Apr 2010 19:00:18 +0100

Citation: KKB Hot Article: Assessing potency of c-Jun N-terminal kinase 3 (JNK3) inhibitors using 2D molecular descriptors and binary QSAR methodology.

Authors: Ijjaali I, Petitet F, Dubus E, Barberan O, Michel A.

PubMed PMID: 17451961

Abstract: JNK3 signaling pathway is gaining interest due to its involvement in many neurological disorders. The purpose of this study was to explore for the first time the use of a large and diverse dataset in combination with binary ...

KKB Hot Article: Molecular modeling studies of vascular endothelial growth factor receptor ...

Tue, 20 Apr 2010 18:56:06 +0100

Citation: Molecular modeling studies of vascular endothelial growth factor receptor tyrosine kinase inhibitors using QSAR and docking

Authors: Du J, Lei B, Qin J, Liu H, Yao X.

PubMed PMID: 19081278

Abstract: The vascular endothelial growth factor (VEGF) and its receptor tyrosine kinases VEGFR-2 or kinase insert domain receptor (KDR) are attractive targets for the development of novel anticancer agents. In the present work, comparative molecular field analysis (CoMFA...

KKB Hot Article: ATP non-competitive IGF-1 receptor kinase inhibitors as lead anti-neoplastic ...

Tue, 20 Apr 2010 18:52:39 +0100

Citation: ATP non-competitive IGF-1 receptor kinase inhibitors as lead anti-neoplastic and anti-papilloma agents.

Authors: Steiner L, Blum G, Friedmann Y, Levitzki A.

PubMed PMID: 17376430

Abstract: The insulin-like growth factor-1 receptor (IGF-1 receptor) is a receptor tyrosine kinase, highly homologous to the insulin receptor. In contrast to the insulin receptor, which is mostly involved in metabolic pathways, the IGF-1 system plays a pivotal role in normal and ne...

KKB Hot Article: Features of selective kinase inhibitors.

Tue, 20 Apr 2010 18:48:52 +0100

Citation: Features of Selective Kinase Inhibitors

Authors: Knight ZA, Shokat KM.

PubMed PMID: 15975507

Abstract: Small-molecule inhibitors of protein and lipid kinases have emerged as indispensable tools for studying signal transduction. Despite the widespread use of these reagents, there is little consensus about the biochemical criteria that define their potency and selectivity in cells. We discuss some of the features that determine the cellular activity of kinase...

KKB Hot Article: 3D-QSAR CoMFA Study on Oxindole Derivatives as Cyclin Dependent Kinase 1 ...

Tue, 20 Apr 2010 18:43:51 +0100

Citation: 3D-QSAR CoMFA study on oxindole derivatives as cyclin dependent kinase 1 (CDK1) and cyclin dependent kinase 2 (CDK2) inhibitors.

Authors: Singh SK, Dessalew N, Bharatam PV.

PubMed PMID: 17266627

Abstract:
Cyclin dependent kinases have emerged as important drug targets with a multitude of therapeutic potentials for their inhibitors. With the purpose of designing new chemical entities with enhanced inhibitory potencies against cyclin dependent kinase 2 (CDK2) and cy...

KKB Hot Article: Seliciclib (CYC202, R-Roscovitine) Induces Cell Death in Multiple Myeloma ...

Tue, 20 Apr 2010 18:40:33 +0100

Citation: Seliciclib (CYC202, R-Roscovitine) Induces Cell Death in Multiple Myeloma Cells by Inhibition of RNA Polymerase II-Dependent Transcription and Down-regulation of Mcl-1

Authors: MacCallum DE, Melville J, Frame S, Watt K, Anderson S, Gianella-Borradori A, Lane DP, Green SR.

PubMed PMID: 15958589

Abstract: Seliciclib (CYC202, R-roscovitine) is a cyclin-dependent kinase (CDK) inhibitor that competes for the ATP binding site on the kinase. It has greatest activity agai...

KKB Hot Article: 3D QSAR studies on a series of potent and high selective inhibitors for three ...

Tue, 20 Apr 2010 18:34:49 +0100

Citation: 3D QSAR studies on a series of potent and high selective inhibitors for three kinases of RTK family

Authors: Cao H, Zhang H, Zheng X, Gao D.

PubMed PMID: 17293140

Abstract:
For targets belonging to the same family of receptors, inhibitors often act at more than one biological target and produce a synergistic effect. Separate CoMFA and CoMSIA models were developed from our data set for the KDR, cKit and Tie-2 inhibitors. These models showed excellent internal pred...

KKB Hot Article: Pharmacological Inhibitors of Glycogen Synthase Kinase 3

Tue, 20 Apr 2010 18:28:56 +0100

Citation: Pharmacological inhibitors of glycogen synthase kinase 3.

Authors: Meijer L, Flajolet M, Greengard P.

PubMed PMID: 15559249

Abstract: Three closely related forms of glycogen synthase kinase 3 (GSK-3alpha, GSK-3beta and GSK-3beta2) have a major role in Wnt and Hedgehog signaling pathways and regulate the cell-division cycle, stem-cell renewal and differentiation, apoptosis, circadian rhythm, transcription and insulin action. A large body of evidence supports specul...

KKB Hot Article: Global Target Profile of the Kinase Inibitor Bosutinib in Primary Chronic ...

Tue, 20 Apr 2010 17:59:16 +0100

Citation: Global Target Profile of the Kinase Inibitor Bosutinib in Primary Chronic Myeloid Leukemia Cells

Authors:
Remsing Rix LL, Rix U, Colinge J, Hantschel O, Bennett KL, Stranzl T, Müller A, Baumgartner C, Valent P, Augustin M, Till JH, Superti-Furga G.

PubMed PMID: 19039322

Abstract:
The detailed molecular mechanism of action of second-generation BCR-ABL tyrosine kinase inhibitors, including perturbed targets and pathways, should contribute to rationalized ...

KKB Hot Articles: Design, synthesis and biological evaluation of substituted ...

Thu, 15 Oct 2009 01:59:20 +0100

Citation: Design, synthesis and biological evaluation of substituted pyrrolo[2,3-d]pyrimidines as multiple receptor tyrosine kinase inhibitors and antiangiogenic agents.

Authors:
Gangjee A, Namjoshi OA, Yu J, Ihnat MA, Thorpe JE, Warnke LA.

PubMed PMID: 18467105

Abstract:
This article reports the design and synthesis of N4-phenylsubstituted-6-(2-phenylethylsubstituted)-7H-pyrrolo[2,3-d]pyrimidine 2,4-diamines as RTK inhibitors. The biological evaluation showed several ana...

KKB Hot Article: Synthesis and biological testing of purine derivatives as potential ...

Thu, 15 Oct 2009 01:54:05 +0100

Citation: Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors.

Authors:
Laufer SA, Domeyer DM, Scior TR, Albrecht W, Hauser DR.

PubMed PMID: 15689155

Abstract:
This article represents the use and the importance of purine moiety to design new kinase inhibitors. Several compounds were designed by simple substitution and combination of purine system (adenine) from original cosubstrate ATP with phenyl moieties. Protein-l...

KKB Hot Article: Specificity and mechanism of action of some commonly used protein kinase ...

Thu, 15 Oct 2009 01:46:40 +0100

Citation: Specificity and mechanism of action of some commonly used protein kinase inhibitors.

Authors:
Davies SP, Reddy H, Caivano M, Cohen P.

PubMed PMID: 10998351

Abstrac:
This article reviews the specificities of 28 commercially available compounds against a large panel of serine/threonine protein kinases. The compounds KT 5720, Rottlerin and quercetin were found to inhibit many kinases, sometimes much more potently than their presumed targets, and conclusions ...

KKB Hot Article: Assessment of Chemical Coverage of Kinome Space and Its Implications for ...

Wed, 14 Oct 2009 16:41:36 +0100

Citation: Assessment of Chemical Coverage of Kinome Space and Its Implications for Kinase Drug Discovery

Authors:
Bamborough;Drewry;Harper;Smith;Schneider

PubMed PMID: 19035792

Abstract:
The ability to carry out high-throughput profiling of compounds against panels of kinases has the potential to change the way that inhibitors are selected and optimized. A total of 577 compounds have been screened against 203 kinases. The set of compounds is representative of a corporate...

KKB Hot Article: A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases.

Wed, 14 Oct 2009 16:22:03 +0100

Citation: A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases

Authors:
Fedorov, Oleg; Marsden, Brian; Pogacic, Vanda; Rellos, Peter; Müller, Susanne; Bullock, Alex N.; Schwaller, Juerg; Sundström, Michael*; Knapp, Stefan

PubMed PMID: 18077363

Abstract:
The study presented here provides publicly available data for a set of 156 widely used kinase inhibitors versus a sizeable panel of...

KKB Hot Article: A small molecule−kinase interaction map for clinical kinase inhibitors

Wed, 14 Oct 2009 16:12:31 +0100

Citation: A small molecule−kinase interaction map for clinical kinase inhibitors

Authors:
Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lélias JM, Mehta SA, Milanov ZV, Velasco AM, Wodicka LM, Patel HK, Zarrinkar PP, Lockhart DJ.

PubMed PMID: 15711537

Abstract:
Kinase inhibitors show great promise as a new class of therapeutics. This article describ...

KKB Hot Article: A quantitative analysis of kinase inhibitor selectivity

Tue, 13 Oct 2009 04:06:47 +0100

Citation: A quantitative analysis of kinase inhibitor selectivity

Authors:
Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP.

PubMed PMID: 18183025

Abstract:
Authors have reported the interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >...

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