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James F Blake,
Rui Xu,
Josef R Bencsik,
Dengming Xiao, Nicholas C Kallan,
Stephen Schlachter,
Ian S Mitchell,
Keith L Spencer,
Anna L Banka,
Eli M Wallace, [......],
Birong Zhang,
Christine Chabot,
Steven Do,
Leslie Lee,
Jason Oeh,
Deepak Sampath,
Brian B Lee,
Kui Lin,
Bianca M Liederer,
Nicholas J Skelton
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ABSTRACT: The discovery and optimization of a series of 6,7-dihydro-5H-cyclopenta[d]pyrimidine compounds that are ATP-competitive, selective inhibitors of protein kinase B/Akt is reported. The initial design and optimization was guided by the use of X-ray structures of inhibitors in complex with Akt1 and the closely related protein kinase A. The resulting compounds demonstrate potent inhibition of all three Akt isoforms in biochemical assays and poor inhibition of other members of the cAMP-dependent protein kinase/protein kinase G/protein kinase C extended family and block the phosphorylation of multiple downstream targets of Akt in human cancer cell lines. Biological studies with one such compound, 28 (GDC-0068), demonstrate good oral exposure resulting in dose-dependent pharmacodynamic effects on downstream biomarkers and a robust antitumor response in xenograft models in which the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway is activated. 28 is currently being evaluated in human clinical trials for the treatment of cancer.
Journal of Medicinal Chemistry 08/2012; 55(18):8110-27. · 4.80 Impact Factor
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Amir T Fathi,
Omotayo Arowojolu,
Ian Swinnen,
Takashi Sato,
Trivikram Rajkhowa,
Donald Small,
Fredrik Marmsater,
John E Robinson,
Stefan David Gross,
Matthew Martinson,
Shelley Allen, Nicholas C Kallan,
Mark Levis
[show abstract]
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ABSTRACT: Patients with acute myeloid leukemia (AML) and a FLT3 internal tandem duplication (ITD) mutation have a poor prognosis, and FLT3 inhibitors are now under clinical investigation. PIM1, a serine/threonine kinase, is up-regulated in FLT3-ITD AML and may be involved in FLT3-mediated leukemogenesis. We employed a PIM1 inhibitor, AR00459339 (Array Biopharma Inc.), to investigate the effect of PIM1 inhibition in FLT3-mutant AML. Like FLT3 inhibitors, AR00459339 was preferentially cytotoxic to FLT3-ITD cells, as demonstrated in the MV4-11, Molm-14, and TF/ITD cell lines, as well as 12 FLT3-ITD primary samples. Unlike FLT3 inhibitors, AR00459339 did not suppress phosphorylation of FLT3, but did promote the de-phosphorylation of downstream FLT3 targets, STAT5, AKT, and BAD. Combining AR00459339 with a FLT3 inhibitor resulted in additive to mildly synergistic cytotoxic effects. AR00459339 was cytotoxic to FLT3-ITD samples from patients with secondary resistance to FLT3 inhibitors, suggesting a novel benefit to combining these agents. We conclude that PIM1 appears to be closely associated with FLT3 signaling, and that inhibition of PIM1 may hold therapeutic promise, either as monotherapy, or by overcoming resistance to FLT3 inhibitors.
Leukemia research 07/2011; 36(2):224-31. · 2.36 Impact Factor
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Nicholas C Kallan,
Keith L Spencer,
James F Blake,
Rui Xu,
Justin Heizer,
Josef R Bencsik,
Ian S Mitchell,
Susan L Gloor,
Matthew Martinson,
Tyler Risom,
Stefan D Gross,
Tony H Morales,
Wen-I Wu,
Guy P A Vigers,
Barbara J Brandhuber,
Nicholas J Skelton
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ABSTRACT: A novel series of spirochromane pan-Akt inhibitors is reported. SAR optimization furnished compounds with improved enzyme potencies and excellent selectivity over the related AGC kinase PKA. Attempted replacement of the phenol hinge binder provided compounds with excellent Akt enzyme and cell activities but greatly diminished selectivity over PKA.
Bioorganic & medicinal chemistry letters 02/2011; 21(8):2410-4. · 2.65 Impact Factor
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Rui Xu,
Anna Banka,
James F Blake,
Ian S Mitchell,
Eli M Wallace,
Josef R Bencsik, Nicholas C Kallan,
Keith L Spencer,
Susan L Gloor,
Matthew Martinson,
Tyler Risom,
Stefan D Gross,
Tony H Morales,
Wen-I Wu,
Guy P A Vigers,
Barbara J Brandhuber,
Nicholas J Skelton
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ABSTRACT: We describe the design and synthesis of novel bicyclic spiro sulfonamides as potent Akt inhibitors. Through structure-based rational design, we have successfully improved PKA selectivity of previously disclosed spirochromanes. Representative compounds showed favorable Akt potency while exhibiting up to 1000-fold selectivity against PKA.
Bioorganic & medicinal chemistry letters 02/2011; 21(8):2335-40. · 2.65 Impact Factor
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James F Blake, Nicholas C Kallan,
Dengming Xiao,
Rui Xu,
Josef R Bencsik,
Nicholas J Skelton,
Keith L Spencer,
Ian S Mitchell,
Richard D Woessner,
Susan L Gloor,
Tyler Risom,
Stefan D Gross,
Matthew Martinson,
Tony H Morales,
Guy P A Vigers,
Barbara J Brandhuber
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ABSTRACT: The discovery and optimization of a series of pyrrolopyrimidine based protein kinase B (Pkb/Akt) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent inhibition of all three Akt isoforms and knockdown of phospho-PRAS40 levels in LNCaP cells and tumor xenografts.
Bioorganic & medicinal chemistry letters 10/2010; 20(19):5607-12. · 2.65 Impact Factor
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Josef R Bencsik,
Dengming Xiao,
James F Blake, Nicholas C Kallan,
Ian S Mitchell,
Keith L Spencer,
Rui Xu,
Susan L Gloor,
Matthew Martinson,
Tyler Risom,
Richard D Woessner,
Faith Dizon,
Wen-I Wu,
Guy P A Vigers,
Barbara J Brandhuber,
Nicholas J Skelton,
Wei Wei Prior,
Lesley J Murray
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ABSTRACT: Herein we report the discovery and synthesis of a novel series of dihydrothieno- and dihydrofuropyrimidines (2 and 3) as potent pan Akt inhibitors. Utilizing previous SAR and analysis of the amino acid sequences in the binding site we have designed inhibitors displaying increased PKA and general kinase selectivity with improved tolerability compared to the progenitor pyrrolopyrimidine (1). A representative dihydrothieno compound (34) was advanced into a PC3-NCI prostate mouse tumor model in which it demonstrated a dose-dependent reduction in tumor growth and stasis when dosed orally daily at 200 mg/kg.
Bioorganic & medicinal chemistry letters 09/2010; 20(23):7037-41. · 2.65 Impact Factor
