Discovery of (Thienopyrimidin-2-yl)aminopyrimidines as Potent, Selective, and Orally Available Pan-PI3-Kinase and Dual Pan-PI3-Kinase/mTOR Inhibitors for the Treatment of Cancer

Sutherlin, Daniel P.; Sampath, Deepak; Berry, Megan; Castanedo, Georgette; Chang, Zhigang; Chuckowree, Irina; Dotson, Jenna; Folkes, Adrian; Friedman, Lori S.; Goldsmith, Richard; Heffron, Tim; Lee, Leslie; Lesnick, John; Lewis, Cristina; Mathieu, Simon; Nonomiya, Jim; Olivero, Alan G.; Pang, Jodie; Prior, Wei Wei; Salphati, Laurent; Sideris, Steve; Tian, Qingping; Tsui, Vickie; Wan, Nan Chi; Wang, Shumei; Wiesmann, Christian; Wong, Susan; Zhu, Bing‐Yan

doi:10.1021/jm901284w

Cited by 113 publications

(102 citation statements)

References 18 publications

(33 reference statements)

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“…The morpholine oxygen functions as a hydrogen bond acceptor with the backbone amino group of Val 851 in the hinge domain of the PI3K p110a isoform. A similar interaction is observed in all the published structures with ATP and with known inhibitors (23,24). The 6-pyridyl exocyclic nitrogen (as a donor) binds to Asp 810 and Asp 933 in the catalytic region.…”

Section: Resultssupporting

confidence: 76%

Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Maira

Pecchi

Huang

et al. 2012

Molecular Cancer Therapeutics

466

382

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Following the discovery of NVP-BEZ235, our first dual pan-PI3K/mTOR clinical compound, we sought to identify additional phosphoinositide 3-kinase (PI3K) inhibitors from different chemical classes with a different selectivity profile. The key to achieve these objectives was to couple a structure-based design approach with intensive pharmacologic evaluation of selected compounds during the medicinal chemistry optimization process. Here, we report on the biologic characterization of the 2-morpholino pyrimidine derivative pan-PI3K inhibitor NVP-BKM120. This compound inhibits all four class I PI3K isoforms in biochemical assays with at least 50-fold selectivity against other protein kinases. The compound is also active against the most common somatic PI3Ka mutations but does not significantly inhibit the related class III (Vps34) and class IV (mTOR, DNA-PK) PI3K kinases. Consistent with its mechanism of action, NVP-BKM120 decreases the cellular levels of p-Akt in mechanistic models and relevant tumor cell lines, as well as downstream effectors in a concentrationdependent and pathway-specific manner. Tested in a panel of 353 cell lines, NVP-BKM120 exhibited preferential inhibition of tumor cells bearing PIK3CA mutations, in contrast to either KRAS or PTEN mutant models. NVP-BKM120 shows dose-dependent in vivo pharmacodynamic activity as measured by significant inhibition of p-Akt and tumor growth inhibition in mechanistic xenograft models. NVP-BKM120 behaves synergistically when combined with either targeted agents such as MEK or HER2 inhibitors or with cytotoxic agents such as docetaxel or temozolomide. The pharmacological, biologic, and preclinical safety profile of NVP-BKM120 supports its clinical development and the compound is undergoing phase II clinical trials in patients with cancer. Mol Cancer Ther; 11(2); 317-28. Ó2011 AACR.

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Section: Resultssupporting

confidence: 76%

Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Maira

Pecchi

Huang

et al. 2012

Molecular Cancer Therapeutics

466

382

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“…S1. The phosphoinositide 3-kinase (PI3K) inhibitors and BRAF inhibitors used in this study were provided by the Genentech Medicinal Chemistry department and have been described previously (16)(17)(18). The structures of the ERK, MEK, PI3K, and BRAF inhibitors used are provided.…”

Section: Compounds and Cell Viability Experimentsmentioning

confidence: 99%

“…S2). Differential effects between parental and MEK-R cells seemed specific to MEK inhibition, as both lines responded similarly when screened with a panel of other targeted and chemotherapeutic agents, including PI3 kinase inhibitors (18,29), the HSP90 inhibitor geldanamycin, and chemotherapeutics such as paclitaxel and etoposide ( Supplementary Fig. S2).…”

Section: Selection Of Mek-resistant Basal-like Breast Cancer Cellsmentioning

confidence: 99%

ERK Inhibition Overcomes Acquired Resistance to MEK Inhibitors

Hatzivassiliou¹,

Liu²,

O’Brien³

et al. 2012

Molecular Cancer Therapeutics

186

153

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The RAS/RAF/MEK pathway is activated in more than 30% of human cancers, most commonly via mutation in the K-ras oncogene and also via mutations in BRAF. Several allosteric mitogen-activated protein/ extracellular signal-regulated kinase (MEK) inhibitors, aimed at treating tumors with RAS/RAF pathway alterations, are in clinical development. However, acquired resistance to these inhibitors has been documented both in preclinical and clinical samples. To identify strategies to overcome this resistance, we have derived three independent MEK inhibitor-resistant cell lines. Resistance to allosteric MEK inhibitors in these cell lines was consistently linked to acquired mutations in the allosteric binding pocket of MEK. In one cell line, concurrent amplification of mutant K-ras was observed in conjunction with MEK allosteric pocket mutations. Clonal analysis showed that both resistance mechanisms occur in the same cell and contribute to enhanced resistance. Importantly, in all cases the MEK-resistant cell lines retained their addiction to the mitogenactivated protein kinase (MAPK) pathway, as evidenced by their sensitivity to a selective inhibitor of the ERK1/2 kinases. These data suggest that tumors with acquired MEK inhibitor resistance remain dependent on the MAPK pathway and are therefore sensitive to inhibitors that act downstream of the mutated MEK target. Importantly, we show that dual inhibition of MEK and ERK by small molecule inhibitors was synergistic and acted to both inhibit the emergence of resistance, as well as to overcome acquired resistance to MEK inhibitors. Therefore, our data provide a rationale for cotargeting multiple nodes within the MAPK signaling cascade in K-ras mutant tumors to maximize therapeutic benefit for patients.

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“…This scaffold shows a broad spectrum of biological activities. The thienopyrimidines were assessed as antitumour [6][7][8][9], medicine [10], enzyme [11][12][13][14], phosphodiesterase inhibitors [15], antioxidative [16,17], antimalarial drug [18,19], antibacterial drug [20], antiviral [21], antifungal [22,23], medication [24], antiplatelet [25] and medicament [26]. In view of these observations, the varied biological property of thienopyrimidine pharmacophore impelled to synthesize the title compounds.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antibacterial Activity of Thienopyrimidine Amide Derivatives

Tharikoppula¹,

Eppakayala²,

Chary³

et al. 2017

Asian J. Chem.

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Thienopyrimidine amide derivatives are important class of organic compounds and show wide range of biological activity. Hence the researchers are paying more attention towards the synthesis of these compounds. A series of thienopyrimidine amide derivatives (13a-m) were synthesized. The newly synthesized amide derivatives (13a-m) were characterized by 1 H NMR, 13C NMR, Mass and IR spectral data. Further these compounds were also evaluated for their antibacterial activity.

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Discovery of (Thienopyrimidin-2-yl)aminopyrimidines as Potent, Selective, and Orally Available Pan-PI3-Kinase and Dual Pan-PI3-Kinase/mTOR Inhibitors for the Treatment of Cancer

Cited by 113 publications

References 18 publications

Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

ERK Inhibition Overcomes Acquired Resistance to MEK Inhibitors

Synthesis and Antibacterial Activity of Thienopyrimidine Amide Derivatives

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