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Hayla Karen Sluss - One of the best experts on this subject based on the ideXlab platform.
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Loss of p53 Ser18 and Atm results in embryonic lethality without cooperation in tumorigenesis.
PloS one, 2011Co-Authors: Heather L. Armata, Punita Shroff, David S. Garlick, Krista L. Penta, Andrew R. Tapper, Hayla Karen SlussAbstract:Phosphorylation at murine Serine 18 (human Serine 15) is a critical regulatory process for the tumor suppressor function of p53. p53Ser18 residue is a substrate for ataxia-telangiectasia mutated (ATM) and ATM-related (ATR) Protein kinases. Studies of mice with a germ-line mutation that replaces Ser18 with Ala (p53S18A mice) have demonstrated that loss of phosphorylation of p53Ser18 leads to the development of tumors, including lymphomas, fibrosarcomas, leukemia and leiomyosarcomas. The predominant lymphoma is B-cell lymphoma, which is in contrast to the lymphomas observed in Atm−/− animals. This observation and the fact that multiple kinases phosphorylate p53Ser18 suggest Atm-independent tumor suppressive functions of p53Ser18. Therefore, in order to examine p53Ser18 function in relationship to ATM, we analyzed the lifespan and tumorigenesis of mice with combined mutations in p53Ser18 and Atm. Surprisingly, we observed no cooperation in survival and tumorigenesis in compound p53S18A and Atm−/− animals. However, we observed embryonic lethality in the compound mutant animals. In addition, the homozygous p53Ser18 mutant allele impacted the weight of Atm−/− animals. These studies examine the genetic interaction of p53Ser18 and Atm in vivo. Furthermore, these studies demonstrate a role of p53Ser18 in regulating embryonic survival and motor coordination.
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The ataxia telangiectasia-mutated target site Ser18 is required for p53-mediated tumor suppression.
Cancer Research, 2007Co-Authors: Heather L. Armata, David S. Garlick, Hayla Karen SlussAbstract:The p53 tumor suppressor is phosphorylated at multiple sites within its NH2-terminal region. One of these phosphorylation sites (mouse Ser18 and human Ser15) is a substrate for the ataxia telangiectasia–mutated (ATM) and ATM-related (ATR) Protein kinases. Studies of p53S18A mice (with a germ-line mutation that replaces Ser18 with Ala) have indicated that ATM/ATR phosphorylation of p53 Ser18 is required for normal DNA damage–induced PUMA expression and apoptosis but not for DNA damage–induced cell cycle arrest. Unlike p53-null mice, p53S18A mice did not succumb to early-onset tumors. This finding suggested that phosphorylation of p53 Ser18 was not required for p53-dependent tumor suppression. Here we report that the survival of p53S18A mice was compromised and that they spontaneously developed late-onset lymphomas (between ages 1 and 2 years). These mice also developed several malignancies, including fibrosarcoma, leukemia, leiomyosarcoma, and myxosarcoma, which are unusual in p53 mutant mice. Furthermore, we found that lymphoma development was linked with apoptotic defects. In addition, p53S18A animals exhibited several aging-associated phenotypes early, and murine embryonic fibroblasts from these animals underwent early senescence in culture. Together, these data indicate that the ATM/ATR phosphorylation site Ser18 on p53 contributes to tumor suppression in vivo. [Cancer Res 2007;67(24):11696–703]
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The ataxia telangiectasia-mutated target site Ser18 is required for p53-mediated tumor suppression.
Cancer research, 2007Co-Authors: Heather L. Armata, David S. Garlick, Hayla Karen SlussAbstract:The p53 tumor suppressor is phosphorylated at multiple sites within its NH(2)-terminal region. One of these phosphorylation sites (mouse Ser(18) and human Ser(15)) is a substrate for the ataxia telangiectasia-mutated (ATM) and ATM-related (ATR) Protein kinases. Studies of p53(S18A) mice (with a germ-line mutation that replaces Ser(18) with Ala) have indicated that ATM/ATR phosphorylation of p53 Ser(18) is required for normal DNA damage-induced PUMA expression and apoptosis but not for DNA damage-induced cell cycle arrest. Unlike p53-null mice, p53(S18A) mice did not succumb to early-onset tumors. This finding suggested that phosphorylation of p53 Ser(18) was not required for p53-dependent tumor suppression. Here we report that the survival of p53(S18A) mice was compromised and that they spontaneously developed late-onset lymphomas (between ages 1 and 2 years). These mice also developed several malignancies, including fibrosarcoma, leukemia, leiomyosarcoma, and myxosarcoma, which are unusual in p53 mutant mice. Furthermore, we found that lymphoma development was linked with apoptotic defects. In addition, p53(S18A) animals exhibited several aging-associated phenotypes early, and murine embryonic fibroblasts from these animals underwent early senescence in culture. Together, these data indicate that the ATM/ATR phosphorylation site Ser(18) on p53 contributes to tumor suppression in vivo.
Heather L. Armata - One of the best experts on this subject based on the ideXlab platform.
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Loss of p53 Ser18 and Atm results in embryonic lethality without cooperation in tumorigenesis.
PloS one, 2011Co-Authors: Heather L. Armata, Punita Shroff, David S. Garlick, Krista L. Penta, Andrew R. Tapper, Hayla Karen SlussAbstract:Phosphorylation at murine Serine 18 (human Serine 15) is a critical regulatory process for the tumor suppressor function of p53. p53Ser18 residue is a substrate for ataxia-telangiectasia mutated (ATM) and ATM-related (ATR) Protein kinases. Studies of mice with a germ-line mutation that replaces Ser18 with Ala (p53S18A mice) have demonstrated that loss of phosphorylation of p53Ser18 leads to the development of tumors, including lymphomas, fibrosarcomas, leukemia and leiomyosarcomas. The predominant lymphoma is B-cell lymphoma, which is in contrast to the lymphomas observed in Atm−/− animals. This observation and the fact that multiple kinases phosphorylate p53Ser18 suggest Atm-independent tumor suppressive functions of p53Ser18. Therefore, in order to examine p53Ser18 function in relationship to ATM, we analyzed the lifespan and tumorigenesis of mice with combined mutations in p53Ser18 and Atm. Surprisingly, we observed no cooperation in survival and tumorigenesis in compound p53S18A and Atm−/− animals. However, we observed embryonic lethality in the compound mutant animals. In addition, the homozygous p53Ser18 mutant allele impacted the weight of Atm−/− animals. These studies examine the genetic interaction of p53Ser18 and Atm in vivo. Furthermore, these studies demonstrate a role of p53Ser18 in regulating embryonic survival and motor coordination.
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The ataxia telangiectasia-mutated target site Ser18 is required for p53-mediated tumor suppression.
Cancer Research, 2007Co-Authors: Heather L. Armata, David S. Garlick, Hayla Karen SlussAbstract:The p53 tumor suppressor is phosphorylated at multiple sites within its NH2-terminal region. One of these phosphorylation sites (mouse Ser18 and human Ser15) is a substrate for the ataxia telangiectasia–mutated (ATM) and ATM-related (ATR) Protein kinases. Studies of p53S18A mice (with a germ-line mutation that replaces Ser18 with Ala) have indicated that ATM/ATR phosphorylation of p53 Ser18 is required for normal DNA damage–induced PUMA expression and apoptosis but not for DNA damage–induced cell cycle arrest. Unlike p53-null mice, p53S18A mice did not succumb to early-onset tumors. This finding suggested that phosphorylation of p53 Ser18 was not required for p53-dependent tumor suppression. Here we report that the survival of p53S18A mice was compromised and that they spontaneously developed late-onset lymphomas (between ages 1 and 2 years). These mice also developed several malignancies, including fibrosarcoma, leukemia, leiomyosarcoma, and myxosarcoma, which are unusual in p53 mutant mice. Furthermore, we found that lymphoma development was linked with apoptotic defects. In addition, p53S18A animals exhibited several aging-associated phenotypes early, and murine embryonic fibroblasts from these animals underwent early senescence in culture. Together, these data indicate that the ATM/ATR phosphorylation site Ser18 on p53 contributes to tumor suppression in vivo. [Cancer Res 2007;67(24):11696–703]
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The ataxia telangiectasia-mutated target site Ser18 is required for p53-mediated tumor suppression.
Cancer research, 2007Co-Authors: Heather L. Armata, David S. Garlick, Hayla Karen SlussAbstract:The p53 tumor suppressor is phosphorylated at multiple sites within its NH(2)-terminal region. One of these phosphorylation sites (mouse Ser(18) and human Ser(15)) is a substrate for the ataxia telangiectasia-mutated (ATM) and ATM-related (ATR) Protein kinases. Studies of p53(S18A) mice (with a germ-line mutation that replaces Ser(18) with Ala) have indicated that ATM/ATR phosphorylation of p53 Ser(18) is required for normal DNA damage-induced PUMA expression and apoptosis but not for DNA damage-induced cell cycle arrest. Unlike p53-null mice, p53(S18A) mice did not succumb to early-onset tumors. This finding suggested that phosphorylation of p53 Ser(18) was not required for p53-dependent tumor suppression. Here we report that the survival of p53(S18A) mice was compromised and that they spontaneously developed late-onset lymphomas (between ages 1 and 2 years). These mice also developed several malignancies, including fibrosarcoma, leukemia, leiomyosarcoma, and myxosarcoma, which are unusual in p53 mutant mice. Furthermore, we found that lymphoma development was linked with apoptotic defects. In addition, p53(S18A) animals exhibited several aging-associated phenotypes early, and murine embryonic fibroblasts from these animals underwent early senescence in culture. Together, these data indicate that the ATM/ATR phosphorylation site Ser(18) on p53 contributes to tumor suppression in vivo.
David Cortez - One of the best experts on this subject based on the ideXlab platform.
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analysis of mutations that dissociate g2 and essential s phase functions of human ataxia telangiectasia mutated and rad3 related ATR Protein kinase
Journal of Biological Chemistry, 2011Co-Authors: Runxiang Zhao, David CortezAbstract:Abstract ATR contains 16 conserved candidate autophosphorylation sites that match its preferred S/TQ consensus. To determine if any are functionally important, we mutated the 16 candidate residues to alanine in a single cDNA to create a 16A-ATR mutant. The 16A-ATR mutant maintains kinase and G2 checkpoint activities. However, it fails to rescue the essential function of ATR in maintaining cell viability and fails to promote replication recovery from a transient exposure to replication stress. Further analysis identified T1566A/T1578A/T1589A (3A-ATR) as critical mutations causing this separation of function activity. Secondary structure predictions indicate these residues occur in a region between ATR HEAT repeats 31R and 32R that aligns with regions of ATM and DNA-PK containing regulatory autophosphorylation sites. While this region is important for ATR function, the 3A-ATR residues do not appear to be sites of autophosphorylation. Nevertheless, our analysis identifies an important regulatory region of ATR that is shared among the PIKK family of kinases. Furthermore, our data indicates that the essential function of ATR for cell viability is linked to its function in promoting proper replication in the context of replication stress and is independent of G2 checkpoint activity.
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Analysis of mutations that dissociate G(2) and essential S phase functions of human ataxia telangiectasia-mutated and Rad3-related (ATR) Protein kinase.
The Journal of biological chemistry, 2011Co-Authors: Edward A. Nam, Runxiang Zhao, David CortezAbstract:ATR (ataxia telangiectasia-mutated and Rad3-related) contains 16 conserved candidate autophosphorylation sites that match its preferred S/TQ consensus. To determine whether any is functionally important, we mutated the 16 candidate residues to alanine in a single cDNA to create a 16A-ATR mutant. The 16A-ATR mutant maintains kinase and G(2) checkpoint activities. However, it fails to rescue the essential function of ATR in maintaining cell viability and fails to promote replication recovery from a transient exposure to replication stress. Further analysis identified T1566A/T1578A/T1589A (3A-ATR) as critical mutations causing this separation of function activity. Secondary structure predictions indicate that these residues occur in a region between ATR HEAT repeats 31R and 32R that aligns with regions of ATM and DNA-PK containing regulatory autophosphorylation sites. Although this region is important for ATR function, the 3A-ATR residues do not appear to be sites of autophosphorylation. Nevertheless, our analysis identifies an important regulatory region of ATR that is shared among the PI3K-related Protein kinase family. Furthermore, our data indicate that the essential function of ATR for cell viability is linked to its function in promoting proper replication in the context of replication stress and is independent of G(2) checkpoint activity.
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ATR: an essential regulator of genome integrity
Nature reviews. Molecular cell biology, 2008Co-Authors: Karlene A. Cimprich, David CortezAbstract:Genome maintenance is a constant concern for cells, and a coordinated response to DNA damage is required to maintain cellular viability and prevent disease. The ataxia-telangiectasia mutated (ATM) and ATM and RAD3-related (ATR) Protein kinases act as master regulators of the DNA-damage response by signalling to control cell-cycle transitions, DNA replication, DNA repair and apoptosis. Recent studies have provided new insights into the mechanisms that control ATR activation, have helped to explain the overlapping but non-redundant activities of ATR and ATM in DNA-damage signalling, and have clarified the crucial functions of ATR in maintaining genome integrity.
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rapid activation of ATR by ionizing radiation requires atm and mre11
Journal of Biological Chemistry, 2006Co-Authors: Jeremy S Myers, David CortezAbstract:Abstract The ataxia-telangiectasia-mutated (ATM) and ATM- and Rad3-related (ATR) Protein kinases are crucial regulatory Proteins in genotoxic stress response pathways that pause the cell cycle to permit DNA repair. Here we show that Chk1 phosphorylation in response to hydroxyurea and ultraviolet radiation is ATR-dependent and ATM- and Mre11-independent. In contrast, Chk1 phosphorylation in response to ionizing radiation (IR) is dependent on ATR, ATM, and Mre11. The ATR and ATM/Mre11 pathways are generally thought to be separate with ATM activation occurring early and ATR activation occurring as a late response to double strand breaks. However, we demonstrate that ATR is activated rapidly by IR, and ATM and Mre11 enhance ATR signaling. ATR-ATR-interacting Protein recruitment to double strand breaks is less efficient in the absence of ATM and Mre11. Furthermore, IR-induced replication Protein A foci formation is defective in ATM- and Mre11-deficient cells. Thus, ATM and Mre11 may stimulate the ATR signaling pathway by converting DNA damage generated by IR into structures that recruit and activate ATR.
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caffeine inhibits checkpoint responses without inhibiting the ataxia telangiectasia mutated atm and atm and rad3 related ATR Protein kinases
Journal of Biological Chemistry, 2003Co-Authors: David CortezAbstract:Abstract The ataxia-telangiectasia-mutated (ATM) and ATM- and Rad3-related (ATR) kinases regulate cell cycle checkpoints by phosphorylating multiple substrates including the CHK1 and -2 Protein kinases and p53. Caffeine has been widely used to study ATM and ATR signaling because it inhibits these kinases in vitro and overcomes cell cycle checkpoint responses in vivo. Thus, caffeine has been thought to overcome the checkpoint through its ability to prevent phosphorylation of ATM and ATR substrates. Surprisingly, I have found that multiple ATM-ATR substrates including CHK1 and -2 are hyperphosphorylated in cells treated with caffeine and genotoxic agents such as hydroxyurea or ionizing radiation. ATM autophosphorylation in cells is also increased when caffeine is used in combination with inhibitors of replication suggesting that ATM activity is not inhibited in vivo by caffeine. Furthermore, CHK1 hyperphosphorylation induced by caffeine in combination with hydroxyurea is ATR-dependent suggesting that ATR activity is stimulated by caffeine. Finally, the G2/M checkpoint in response to ionizing radiation or hydroxyurea is abrogated by caffeine treatment without a corresponding decrease in ATM-ATR-dependent signaling. This data suggests that although caffeine is an inhibitor of ATM-ATR kinase activity in vitro, it can block checkpoints without inhibiting ATM-ATR activation in vivo.
Abdelilah Aboussekhra - One of the best experts on this subject based on the ideXlab platform.
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ATR controls the UV-related upregulation of the CDKN1A mRNA in a Cdk1/HuR-dependent manner.
Molecular carcinogenesis, 2013Co-Authors: Huda H. Al-khalaf, Abdelilah AboussekhraAbstract:Ultraviolet (UV) light is a carcinogenic agent that upregulates the expression of several genes involved in various cellular processes, including cell cycle checkpoints and apoptosis. The universal cyclin-dependent kinase inhibitor p21WAF1/Cip1 plays major roles in these processes, and the level of its corresponding message increases several times in response to UV-induced DNA damage. This upregulation is mainly posttranscriptional owing to HuR-dependent mRNA stabilization. Since the Protein kinase ATR plays major roles during the cellular response to UV damage, we sought to investigate its possible implication in the stabilization of the p21WAF1/Cip1 coding mRNA. We have shown that the UV-dependent accumulation of the CDKN1A mRNA is indeed under the control of the ATR Protein kinase. Upon UV damage, ATR allows nuclear–cytoplasmic shuttling of the HuR Protein, which binds the CDKN1A mRNA and reduces its turnover. This ATR-dependent effect is mediated through UV-related phosphorylation/inactivation of the Cdk1 Protein kinase by ATR, which leads to the dissociation of HuR from Cdk1. Indeed, inhibition or shRNA specific knockdown of CDK1 in ATR-deficient cells enhanced the cytoplasmic level of HuR and restored the CDKN1A mRNA upregulation in response to UV damage. These results show that ATR stabilizes the CDKN1A message in response to UV damage through Cdk1-related cytoplasmic accumulation of HuR. © 2013 Wiley Periodicals, Inc.
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ATR controls the p21waf1 cip1 Protein up regulation and apoptosis in response to low uv fluences
Molecular Carcinogenesis, 2012Co-Authors: Huda H Alkhalaf, Siti-faujiah Hendrayani, Abdelilah AboussekhraAbstract:The universal cyclin-dependent kinase inhibitor p21(WAF1/Cip1) promotes cell cycle arrest and inhibits apoptosis in response to UV-induced DNA damage. Since the Protein kinase ATR plays a major role in the cellular response to these carcinogenic lesions, we investigated the possible role of ATR in the modulation of p21(WAF1/Cip1) expression in response to UVC radiation. We have shown that p21(WAF1/Cip1) is up-regulated in human fibroblast and epithelial cells, but only in response to low UV fluences and low passage cells. Importantly, this up-regulation is ATR-dependent. In fact, in ATR-deficient or caffeine-treated cells UV light rather down-regulated the p21(WAF1/Cip1) Protein through SKP2-dependent ubiquitination and degradation via the proteasomal pathway. Furthermore, we present evidence that ATR inhibits apoptosis in response to low fluences of UV light, through inhibiting the cleavage of caspase 3 and PARP as well as the repression of the proapoptotic Proteins BAX and BAK. Interestingly, ATR is also required for the stability of the p21(WAF1/Cip1) Protein in absence of genotoxic stress. Together, these results indicate that during the cellular response to low UVC fluences the ATR Protein kinase up-regulates p21(WAF1/Cip1) and inhibits apoptosis. © 2011 Wiley Periodicals, Inc.
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ATR controls the p21WAF1/Cip1 Protein up‐regulation and apoptosis in response to low UV fluences
Molecular carcinogenesis, 2011Co-Authors: Huda H. Al-khalaf, Siti-faujiah Hendrayani, Abdelilah AboussekhraAbstract:The universal cyclin-dependent kinase inhibitor p21(WAF1/Cip1) promotes cell cycle arrest and inhibits apoptosis in response to UV-induced DNA damage. Since the Protein kinase ATR plays a major role in the cellular response to these carcinogenic lesions, we investigated the possible role of ATR in the modulation of p21(WAF1/Cip1) expression in response to UVC radiation. We have shown that p21(WAF1/Cip1) is up-regulated in human fibroblast and epithelial cells, but only in response to low UV fluences and low passage cells. Importantly, this up-regulation is ATR-dependent. In fact, in ATR-deficient or caffeine-treated cells UV light rather down-regulated the p21(WAF1/Cip1) Protein through SKP2-dependent ubiquitination and degradation via the proteasomal pathway. Furthermore, we present evidence that ATR inhibits apoptosis in response to low fluences of UV light, through inhibiting the cleavage of caspase 3 and PARP as well as the repression of the proapoptotic Proteins BAX and BAK. Interestingly, ATR is also required for the stability of the p21(WAF1/Cip1) Protein in absence of genotoxic stress. Together, these results indicate that during the cellular response to low UVC fluences the ATR Protein kinase up-regulates p21(WAF1/Cip1) and inhibits apoptosis. © 2011 Wiley Periodicals, Inc.
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The ATR Protein kinase controls UV-dependent upregulation of p16INK4A through inhibition of Skp2-related polyubiquitination/degradation.
Molecular cancer research : MCR, 2011Co-Authors: Huda H. Al-khalaf, Siti-faujiah Hendrayani, Abdelilah AboussekhraAbstract:The tumor suppressor p16INK4A, a phophoProtein that exists in human cells under both phosphorylated and nonphosphorylated forms, plays crucial roles during the cellular response to UV light. However, it is still unclear how this Protein is activated in response to this carcinogenic agent. We have shown here that UVC up-regulates p16INK4A and the phosphorylated form of the Protein at the 4 serine sites; Ser-7, Ser-8, Ser-140 and Ser-152. This accumulation of p16INK4A occurred through increasing the stability of both forms of the Protein. Importantly, phospho-p16INK4A showed much higher stability, and UV treatment strongly increased its level in absence of de novo Protein synthesis. Furthermore, we have shown that the UV-dependent up-regulation of both forms of p16INK4A is under the control of the Protein kinase ATR, which suppresses their UVC-dependent proteasomal degradation. Interestingly, while this degradation is ubiquitin-related for p16INK4A through the Skp2 ubiquitin ligase Protein, it is ubiquitin-independent for the phosphorylated form. In addition, we present clear evidence that Skp2 is up-regulated in ATR-deficient cells, leading to the down-regulation of the p27Kip1 Protein in response to UVC light. Moreover, we have shown a preferential association of endogeneous phospho-p16INK4A with Cdk4. This association increased following UV-treatment mainly for p16INK4A phosphorylated at Ser-140 and Ser-152. Besides, we have shown that ATR regulates UV-related p16/Cdk4-dependent and -independent phosphorylation of pRB and G1 cell cycle delay. Together, these results indicate that p16INK4A and p27Kip1 are key targets in the ATR-dependent signaling pathway in response to UV damage.
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Abstract P4-05-02: Role of the ATR Protein Kinase and Curcumin in Tumor-Stromal Interactions in Breast Cancer
Poster Session Abstracts, 2010Co-Authors: Abdelilah Aboussekhra, Mysoon M. Al-ansari, S-f Hendrayani, Taher Al-tweigeriAbstract:Carcinoma-associated fibroblasts (CAFs) play important roles in the genesis and thrive of various types of epithelial cancers, including breast carcinomas. Indeed, various genetic and epigenetic variations have been identified in stromal fibroblasts, and we have recently shown that CAFs as well as their corresponding counterparts (TCFs) display neoplastic-specific changes (Hawsawi et al., 2008). We have also shown that the levels of the tumor suppressor Proteins p53 and p21 are down-regulated in CAFs as compared to TCFs. During the cellular response to DNA damage these genes are under the control of important Proteins such as ATR, a Protein kinase essential for the maintenance of genomic integrity. To further elucidate the molecular changes that occur in breast cancer-associated fibroblasts we assessed the expression of ATR and have shown that the level of the ATR Protein kinase is lower in 7 out of 10 (70%) CAFs as compared to their corresponding TCFs. Using specific ATR -siRNA we have shown that ATR negatively controls the expression of various Proteins involved in the stromal-epithelial interactions. These include the stromal cell-derived factor 1 (SDF1), the vascular endothelial growth factor (VEGF) and the mATRix metalloProteinase-2 (MMP2). In addition, the ELISA assay was used to show that the level of these Proteins was higher in the conditioned media from stromal fibroblasts expressing specific ATR- siRNA as compared to control cells. Importantly, serum-free conditioned media from ATR-defective cells stimulated the proliferation and invasion/migration of cultured human breast cancer cells in an SDF1-dependent manner. These results clearly show the role of the breast stromal fibroblast ATR Protein in suppressing tumoregenesis in the breast. Moreover, we have shown that curcumin can normalize the expression/secretion of these factors and therefore reduces the invasion/migration of breast cancer cells in vitro. This indicates that curcumin has potential use as stromal fibroblastnormalizing factor that can be utilized for the inhibition of both cancer initiation and recurrence. Hawsawi, N. M., Ghebeh, H., Hendrayani, S. F., Tulbah, A., Al-Eid, M., Al-Tweigeri, T., Ajarim, D., Alaiya, A., Dermime, S., and Aboussekhra, A. (2008). Cancer Res 68, 2717-2725. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-05-02.
Thomas M. Mcguire - One of the best experts on this subject based on the ideXlab platform.
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Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole (AZ20): A Potent and Selective Inhibitor of ATR Protein Kinase with Monotherapy in Vivo Antitumor Activity
Journal of medicinal chemistry, 2013Co-Authors: Kevin Michael Foote, Kevin Blades, Anna Cronin, Shaun M. Fillery, Sylvie S. Guichard, Lorraine A. Hassall, Ian Hickson, Xavier Jacq, Philip J. Jewsbury, Thomas M. McguireAbstract:ATR is an attractive new anticancer drug target whose inhibitors have potential as chemo- or radiation sensitizers or as monotherapy in tumors addicted to particular DNA-repair pathways. We describe the discovery and synthesis of a series of sulfonylmorpholinopyrimidines that show potent and selective ATR inhibition. Optimization from a high quality screening hit within tight SAR space led to compound 6 (AZ20) which inhibits ATR immunoprecipitated from HeLa nuclear extracts with an IC50 of 5 nM and ATR mediated phosphorylation of Chk1 in HT29 colorectal adenocarcinoma tumor cells with an IC50 of 50 nM. Compound 6 potently inhibits the growth of LoVo colorectal adenocarcinoma tumor cells in vitro and has high free exposure in mouse following moderate oral doses. At well tolerated doses 6 leads to significant growth inhibition of LoVo xenografts grown in nude mice. Compound 6 is a useful compound to explore ATR pharmacology in vivo.
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discovery of 4 4 3r 3 methylmorpholin 4 yl 6 1 methylsulfonyl cyclopropyl pyrimidin 2 yl 1h indole az20 a potent and selective inhibitor of ATR Protein kinase with monotherapy in vivo antitumor activity
Journal of Medicinal Chemistry, 2013Co-Authors: Kevin Michael Foote, Kevin Blades, Anna Cronin, Shaun M. Fillery, Sylvie S. Guichard, Lorraine A. Hassall, Ian Hickson, Xavier Jacq, Philip J. Jewsbury, Thomas M. McguireAbstract:ATR is an attractive new anticancer drug target whose inhibitors have potential as chemo- or radiation sensitizers or as monotherapy in tumors addicted to particular DNA-repair pathways. We describe the discovery and synthesis of a series of sulfonylmorpholinopyrimidines that show potent and selective ATR inhibition. Optimization from a high quality screening hit within tight SAR space led to compound 6 (AZ20) which inhibits ATR immunoprecipitated from HeLa nuclear extracts with an IC50 of 5 nM and ATR mediated phosphorylation of Chk1 in HT29 colorectal adenocarcinoma tumor cells with an IC50 of 50 nM. Compound 6 potently inhibits the growth of LoVo colorectal adenocarcinoma tumor cells in vitro and has high free exposure in mouse following moderate oral doses. At well tolerated doses 6 leads to significant growth inhibition of LoVo xenografts grown in nude mice. Compound 6 is a useful compound to explore ATR pharmacology in vivo.