AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity

Yap, Timothy A.; Walton, Mike I.; Grimshaw, Kyla M.; Poele, Robert H. te; Eve, Paul D.; Valenti, Melanie; Brandon, Alexis K. de Haven; Martins, Vanessa; Zetterlund, Anna; Heaton, Simon P.; Heinzmann, Kathrin; Jones, Paul S.; Feltell, Ruth E.; Reule, Matthias; Woodhead, Steven J.; Davies, Thomas G.; Lyons, John F.; Raynaud, Florence I.; Eccles, Suzanne A.; Workman, Paul; Thompson, Neil T.; Garrett, Michelle D.

doi:10.1158/1078-0432.ccr-11-3313

Cited by 87 publications

(83 citation statements)

References 34 publications

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“…1A). As expected from previous work (16,17), CCT129254 and AT13148 strongly inhibited AKT downstream signaling as shown by the decrease in Thr246 phosphorylation of the proline-rich Akt-substrate (PRAS40). The potency of both compounds toward the inhibition of MLC2 phosphorylation is independent from effects on AKTregulated signaling, as CCT130293, an ATP-competitive inhibitor of AKT that does not inhibit ROCK, and MK-2206, an allosteric inhibitor of AKT, strongly inhibit AKT activity and AKT-downstream signaling but have no effect on phosphorylation of MLC2 (Fig.…”

Section: Cct129254 and At13148 Are Potent Inhibitors Of Rock-driven Asupporting

confidence: 88%

“…Previously reported pharmacokinetic and pharmacodynamic analysis of AT13148 has established an orally administrated dose of 40 mg/kg as the optimal, therapeutically active concentration in male athymic mice (17). Although we could show a consistent impairment of the motility of melanoma tumor cells in culture and in vivo (Fig.…”

Section: Inhibition Of Melanoma Metastasis By Cct129254mentioning

confidence: 52%

“…were generated by infection of the transformed MEFs with Adeno GFP. CCT129254, CCT130293 (16), and AT13148 (17) were synthesized in-house. MK2206 was obtained from ChemieTek, H1152 from MERCK Millipore, and Y27632 from Tocris Bioscience.…”

Section: Methodsmentioning

confidence: 99%

“…Fragment-based screening together with medicinal chemistry has led to the discovery and development of compounds targeting AKT/PKB, including the orally available, ATP-competitive kinase inhibitors AT13148 and CCT129254 (16,17,27). In vitro screening of AT13148 against a panel of kinases shows that it is a multi-AGC kinase inhibitor, with potent activities against ROCK1 (IC 50 Table S1).…”

Section: Cct129254 and At13148 Are Potent Inhibitors Of Rock-driven Amentioning

confidence: 99%

“…In order to identify potent ROCK inhibitors that are active in vivo, we have studied the novel ATP-competitive AKT inhibitors CCT129254 and AT13148, which have been developed to have good pharmacokinetic properties in vivo and potently inhibit ROCK in vitro (16,17). We have carried out these studies in melanoma cells, because previous work has identified key roles for ROCK signaling in invasion of melanoma cells (11,18,19) and we have established an orthotopic model of spontaneous metastasis for assessment of inhibitors in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Rho Kinase Inhibitors Block Melanoma Cell Migration and Inhibit Metastasis

et al. 2015

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There is an urgent need to identify new therapeutic opportunities for metastatic melanoma. Fragment-based screening has led to the discovery of orally available, ATP-competitive AKT kinase inhibitors, AT13148 and CCT129254. These compounds also inhibit the Rho-kinases ROCK 1 and ROCK 2 and we show they potently inhibit ROCK activity in melanoma cells in culture and in vivo. Treatment of melanoma cells with CCT129254 or AT13148 dramatically reduces cell invasion, impairing both "amoeboidlike" and mesenchymal-like modes of invasion in culture. Intravital imaging shows that CCT129254 or AT13148 treatment reduces the motility of melanoma cells in vivo. CCT129254 inhibits melanoma metastasis when administered 2 days after orthotopic intradermal injection of the cells, or when treatment starts after metastases have arisen. Mechanistically, our data suggest that inhibition of ROCK reduces the ability of melanoma cells to efficiently colonize the lungs. These results suggest that these novel inhibitors of ROCK may be beneficial in the treatment of metastasis. Cancer Res; 75(11); 2272-84. Ó2015 AACR.

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Section: Cct129254 and At13148 Are Potent Inhibitors Of Rock-driven Asupporting

confidence: 88%

Section: Inhibition Of Melanoma Metastasis By Cct129254mentioning

confidence: 52%

Section: Methodsmentioning

confidence: 99%

Section: Cct129254 and At13148 Are Potent Inhibitors Of Rock-driven Amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rho Kinase Inhibitors Block Melanoma Cell Migration and Inhibit Metastasis

et al. 2015

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Formation of Tertiary Alcohol via Chelation‐Assisted Nickel(II)‐Catalyzed Addition of Arylboronic Acids to Unactivated 1‐(Quinolin‐8‐yl)ethan‐1‐one

Guo

Wang

et al. 2018

Adv Synth Catal

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The synthesis of tertiary alcohol via chelation‐assisted nickel‐catalyzed addition of arylboronic acids to unactivated ketones was reported in this study. A series of substituted arylboronic acids was reacted with 1‐(quinolin‐8‐yl)ethan‐1‐one and its derivatives to provide various substituted 1‐aryl‐1‐(quinolin‐8‐yl)ethan‐1‐ols and relevant compounds in medium to good yields. The N‐directing group is essential for the addition reaction of arylboronic acids to these unactivated ketones. Nickel(II) acetylacetonate (10.0 mol%) in combination with sodium iodide (2 equiv.) and potassium carbonate (0.8 equiv.) was identified as the optimal catalytic system for the current transformations.magnified image

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Highly Enantioselective Rhodium‐Catalyzed Addition of Arylboroxines to Simple Aryl Ketones: Efficient Synthesis of Escitalopram

et al. 2016

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Highly enantioselective additions of arylboroxines to simple aryl ketones have been achieved for the first time with aR h/(R,R,R,R)-WingPhos catalyst, thus providing ar ange of chiral diaryl alkylcarbinols with excellent ee values and yields. (R,R,R,R)-WingPhos has been proven to be crucial for the high reactivity and enantioselectivity.The method has enabled an ew,c oncise,a nd enantioselective synthesis of the antidepressant drug escitalopram.Chiral diaryl alkyl carbinol moieties exist in an umber of therapeutic agents and natural products, [1] such as the antidepressant escitalopram, [2a] antihistamine clemastine, [2b] cough suppressant chlophedianol, [2c] multi-AGC kinase inhibitor AT13148, [2d] fungicide flutriafol, [2e] and lignan hydroxyotobain [2f] (Figure 1). Thee fficient synthesis of these chiral tertiary alcohols have thus gained ag reat deal of attention. Among the various methods, [3] thec atalytic asymmetric arylations of ketones stand out to be most attractive. [4,5] In particular,a symmetric addition of nontoxic,s table,a nd operationally simple aryl boron reagents to simple unactivated ketones is highly desirable yet remains challenging. Despite the recent advances in asymmetric additions of arylboron reagents to aldehydes, [6] activated ketones, [7] or ketones in an intramolecular fashion, [8] few successful results were reported on asymmetric intermolecular addition of aryl boron reagents to simple ketones.[9] Low enantioseletivities were reported for either chiral nickel or rhodium catalysts (a Ni/chiral N-heterocyclic carbene ligand:3 6% ee,[9a] aR h/ chiral bisphosphine:38%ee, [9b] aRh/chiral diene:68% ee).[9c]Al ow yield was also observed in our previous study,a lbeit with an improved enantioselectivity (25 %y ield, 95 % ee).[7l]To our knowledge,b oth excellent enantioselectivities and yields are yet to be achieved for intermolecular asymmetric additions of aryl boron reagents to simple ketones.Herein we report ah ighly enantioselective rhodium-catalyzed addition of arylboroxines to simple aryl ketones in excellent yields and with up to 99 % ee by using Rh/(R,R,R,R)-WingPhos as the catalyst. This method has enabled an efficient and concise synthesis of the blockbuster antidepressant escitalopram. Ligand design has played ac entral role in the development of efficient metal-catalyzed reactions.[10] Thed esign of chiral phosphorus ligands capable of long-range stereocontrol remain asignificant challenge with limited success.Because of the less reactive nature and low coordinative ability of simple ketones,i nc omparison with aldehydes or imines,t he intermolecular addition of arylboron reagents to simple ketones relies upon the metal catalyst to bring the two reaction partners into close proximity,a sw ell as provide good stereocontrol at ag reater distance from the metal center (Figure 2). Am etal catalyst equipped with ad iphosphine ligand having as hallow chiral pocket (Figure 2a)w ill be inefficient for such ar eaction in terms of both enantioselectivity and reactivit...

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AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity

Cited by 87 publications

References 34 publications

Rho Kinase Inhibitors Block Melanoma Cell Migration and Inhibit Metastasis

Rho Kinase Inhibitors Block Melanoma Cell Migration and Inhibit Metastasis

Formation of Tertiary Alcohol via Chelation‐Assisted Nickel(II)‐Catalyzed Addition of Arylboronic Acids to Unactivated 1‐(Quinolin‐8‐yl)ethan‐1‐one

Highly Enantioselective Rhodium‐Catalyzed Addition of Arylboroxines to Simple Aryl Ketones: Efficient Synthesis of Escitalopram

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