Phosphatidylinositol 3-Kinase (PI3K) and Phosphatidylinositol 3-Kinase-Related Kinase (PIKK) Inhibitors: Importance of the Morpholine Ring

Andrš, Martin; Korábečný, Jan; Jun, Daniel; Hodný, Zdeněk; Bártek, Jiří; Kuča, Kamil

doi:10.1021/jm501026z

Cited by 125 publications

(113 citation statements)

References 243 publications

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“…3B and C) is likely because PI3K and mTOR are related kinases and LY294002 partially inhibits mTOR as well as PI3K. 32 These data demonstrate that the feedback activation of Akt via suppression of mTORC1 26,27 inhibits the apoptotic machinery activated by rapamycin in Calu-1 cells. However, suppression of Akt phosphorylation restores the sensitivity of S-phase cells to rapamycin.…”

Section: Combined Inhibition Of Mtorc1 and Akt Phosphorylation Inducementioning

confidence: 71%

Apoptotic effects of high-dose rapamycin occur in S-phase of the cell cycle

et al. 2015

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Abbreviations: 4E-BP1, eIF4E binding protein-1; eIF4E, eukaryotic initiation factor 4E; Gln, glutamine; GOT, glutamateoxaloacetate-transaminase; mTOR, mammalian target of rapamycin; mTORC1/2, mTOR complex 1/2; PARP, poly-ADP-ribose polymerase; PI3K, phosphatidylinositol-3-kinase; S6K, S6 kinase; TGF-b, transforming growth factor-b.Mutations in genes encoding regulators of mTOR, the mammalian target of rapamycin, commonly provide survival signals in cancer cells. Rapamycin and analogs of rapamycin have been used with limited success in clinical trials to target mTOR-dependent survival signals in a variety of human cancers. Suppression of mTOR predominantly causes G1 cell cycle arrest, which likely contributes to the ineffectiveness of rapamycin-based therapeutic strategies. While rapamycin causes the accumulation of cells in G1, its effect in other cell cycle phases remains largely unexplored. We report here that when synchronized MDA-MB-231 breast cancer cells are allowed to progress into S-phase from G 1 , rapamycin activates the apoptotic machinery with a concomitant increase in cell death. In Calu-1 lung cancer cells, rapamycin induced a feedback increase in Akt phosphorylation at Ser473 in S-phase that mitigated rapamycin-induced apoptosis. However, sensitivity to rapamycin in S-phase could be reestablished if Akt phosphorylation was suppressed. We recently reported that glutamine (Gln) deprivation causes K-Ras mutant cancer cells to aberrantly arrest primarily in S-phase. Consistent with observed sensitivity of S-phase cells to rapamycin, interfering with Gln utilization sensitized both MDA-MB-231 and Calu-1 K-Ras mutant cancer cells to the apoptotic effect of rapamycin. Importantly, rapamycin induced substantially higher levels of cell death upon Gln depletion than that observed in cancer cells that were allowed to progress through S-phase after being synchronized in G 1 . We postulate that exploiting metabolic vulnerabilities in cancer cells such as S-phase arrest observed with K-Ras-driven cancer cells deprived of Gln, could be of great therapeutic potential.

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Section: Combined Inhibition Of Mtorc1 and Akt Phosphorylation Inducementioning

confidence: 71%

Apoptotic effects of high-dose rapamycin occur in S-phase of the cell cycle

et al. 2015

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“…The imidazoline N1 nitrogen forms a critical hydrogen bond to Val882 in the adenine pocket (Figure ). The majority of known PI3Kα inhibitors use a morpholine oxygen for this interaction …”

Section: Resultsmentioning

confidence: 99%

Discovery and SAR of Novel 2,3‐Dihydroimidazo[1,2‐c]quinazoline PI3K Inhibitors: Identification of Copanlisib (BAY 80‐6946)

et al. 2016

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The phosphoinositide 3‐kinase (PI3K) pathway is aberrantly activated in many disease states, including tumor cells, either by growth factor receptor tyrosine kinases or by the genetic mutation and amplification of key pathway components. A variety of PI3K isoforms play differential roles in cancers. As such, the development of PI3K inhibitors from novel compound classes should lead to differential pharmacological and pharmacokinetic profiles and allow exploration in various indications, combinations, and dosing regimens. A screening effort aimed at the identification of PI3Kγ inhibitors for the treatment of inflammatory diseases led to the discovery of the novel 2,3‐dihydroimidazo[1,2‐c]quinazoline class of PI3K inhibitors. A subsequent lead optimization program targeting cancer therapy focused on inhibition of PI3Kα and PI3Kβ. Herein, initial structure–activity relationship findings for this class and the optimization that led to the identification of copanlisib (BAY 80‐6946) as a clinical candidate for the treatment of solid and hematological tumors are described.

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“…Rapid metabolic clearance, instability, in vivo toxicity and off-target effects of wortmannin and LY294002 made further preclinical and clinical evaluation impractical (Collis, DeWeese, Jeggo, & Parker, 2005; Davidson, Amrein, Panasci, & Aloyz, 2013). However, LY294002 has been extensively utilized by KuDOS Pharmaceuticals Ltd. (UK) and Ihmaid et al as a lead compound for further modifications to improve specificity and efficacy to reduce off-target toxicities (Leahy et al, 2004; Clapham et al, 2011; Munck et al, 2012; Ihmaid, Al-Rawi, Bradley, Angove, & Robertson, 2012; Andrs et al, 2015). …”

Section: : Targeting Dna Double Strand Break Repair and Radiation Thmentioning

confidence: 99%

DNA repair targeted therapy: The past or future of cancer treatment?

Gavande

VanderVere-Carozza

Hinshaw

et al. 2016

Pharmacology & Therapeutics

331

282

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The repair of DNA damage is a complex process that relies on particular pathways to remedy specific types of damage to DNA. The range of insults to DNA includes small, modest changes in structure including mismatched bases and simple methylation events to oxidized bases, intra- and interstrand DNA crosslinks, DNA double strand breaks and protein-DNA adducts. Pathways required for the repair of these lesions include mismatch repair, base excision repair, nucleotide excision repair, and the homology directed repair/Fanconi anemia pathway. Each of these pathways contributes to genetic stability, and mutations in genes encoding proteins involved in these pathways have been demonstrated to promote genetic instability and cancer. In fact, it has been suggested all cancers display defects in DNA repair. It has also been demonstrated that the ability of cancer cells to repair therapeutically induced DNA damage impacts therapeutic efficacy. This has led to targeting DNA repair pathways and proteins to develop anti-cancer agents that will increase sensitivity to traditional chemotherapeutics. While initial studies languished and were plagued by a lack of specificity and a defined mechanism of action, more recent approaches to exploit synthetic lethal interaction and develop high affinity chemical inhibitors have proven considerably more effective. In this review we will highlight recent advances and discuss previous failures in targeting DNA repair to pave the way for future DNA repair targeted agents and their use in cancer therapy.

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Phosphatidylinositol 3-Kinase (PI3K) and Phosphatidylinositol 3-Kinase-Related Kinase (PIKK) Inhibitors: Importance of the Morpholine Ring

Cited by 125 publications

References 243 publications

Apoptotic effects of high-dose rapamycin occur in S-phase of the cell cycle

Apoptotic effects of high-dose rapamycin occur in S-phase of the cell cycle

Discovery and SAR of Novel 2,3‐Dihydroimidazo[1,2‐c]quinazoline PI3K Inhibitors: Identification of Copanlisib (BAY 80‐6946)

DNA repair targeted therapy: The past or future of cancer treatment?

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