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Joerg Bussenius,
Charles M Blazey,
Naing Aay,
Neel K Anand,
Arlyn Arcalas,
TaeGon Baik, Owen J Bowles,
Chris A Buhr,
Simona Costanzo,
Jeffrey K Curtis, [......],
Monique Nicoll,
John M Nuss,
Michael Pack,
Csaba J Peto,
Tsze H Tsang,
Longcheng Wang,
Scott W Womble,
Michael Yakes,
Wentao Zhang,
Kenneth D Rice
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ABSTRACT: With structural guidance, tropane-derived HTS hits were modified to optimize for HSP90 inhibition and a desirable in vivo profile. Through an iterative SAR development process 12i (XL888) was discovered and shown to reduce HSP90 client protein content in PD studies. Furthermore, efficacy experiments performed in a NCI-N87 mouse xenograft model demonstrated tumor regression in some dosing regimens.
Bioorganic & medicinal chemistry letters 07/2012; 22(17):5396-404. · 2.65 Impact Factor
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Joerg Bussenius,
Neel K Anand,
Charles M Blazey, Owen J Bowles,
Lynne Canne Bannen,
Diva S-M Chan,
Baili Chen,
Erick W Co,
Simona Costanzo,
Steven C DeFina, [......],
David J Matthews,
David Markby,
Nicole Miller,
John M Nuss,
Jason J Parks,
Tsze H Tsang,
Amy L Tsuhako,
Yong Wang,
Wei Xu,
Kenneth D Rice
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ABSTRACT: The 70-kDa ribosomal protein S6 kinase (p70S6K) is part of the PI3K/AKT/mTOR pathway and has been implicated in cancer. High throughput screening versus p70S6K led to the identification of aminopyrimidine 3a as active inhibitor. Lead optimization of 3a resulted in highly potent, selective, and orally bioavailable pyrazolopyrimidines. In this manuscript we report the structure-activity relationship of this series and pharmacokinetic, pharmacodynamic, and efficacy data of the lead compound 13c.
Bioorganic & medicinal chemistry letters 03/2012; 22(6):2283-6. · 2.65 Impact Factor
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Kenneth D Rice,
Moon H Kim,
Joerg Bussenius,
Neel K Anand,
Charles M Blazey, Owen J Bowles,
Lynne Canne-Bannen,
Diva S-M Chan,
Baili Chen,
Erick W Co, [......],
Morrison B Mac,
David J Matthews,
David Markby,
Nicole Miller,
John M Nuss,
Jason J Parks,
Tsze H Tsang,
Amy L Tsuhako,
Yong Wang,
Wei Xu
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ABSTRACT: Activation of the PI3K/Akt/mTOR kinase pathway is frequently associated with human cancer. Selective inhibition of p70S6Kinase, which is the last kinase in the PI3K pathway, is not sufficient for strong tumor growth inhibition and can lead to activation of upstream proteins including Akt through relief of a negative feedback loop. Targeting multiple sites in the PI3K pathway might be beneficial for optimal activity. In this manuscript we report the design of dual Akt/p70S6K inhibitors and the evaluation of the lead compound 11b in vivo, which was eventually advanced into clinical development.
Bioorganic & medicinal chemistry letters 03/2012; 22(8):2693-7. · 2.65 Impact Factor
