Bayard R. Huck

SAR and evaluation of novel 5H-benzo[c][1,8]naphthyridin-6-one analogs as Aurora kinase inhibitors

Several potent Aurora kinase inhibitors derived from 5H-benzo[c][1,8]naphthyridin-6-one scaffold were identified. A crystal structure of Aurora kinase A in complex with an initial hit revealed a binding mode of the inhibitor within the ATP binding site and provided insight for structure-guided compound optimization. Subsequent SAR campaign provided a potent and selective pan Aurora inhibitor, which demonstrated potent target modulation and antiproliferative effects in the pancreatic cell line, MIAPaCa-2. Furthermore, this compound inhibited phosphorylation of histone H3 (pHH3) in mouse bone morrow upon oral administration, which is consistent with inhibition of Aurora kinase B activity.

Abstract 4516: Evaluation of p70S6K/Akt inhibitor MSC2363318A in patient derived xenograft (PDX) models of breast cancer

The PI3K pathway is involved in the regulation of cell growth, proliferation, metabolism and other functions. Aberrant signaling (PTEN loss of function, PIK3CA mutation, Akt amplification, etc.) from the PI3K pathway is observed in >50% of all tumors. Clinical evidence suggests that inhibiting the PI3K pathway is beneficial for the treatment of solid tumors and tumors of the hematopoietic system. Inhibition of mTOR via rapalogs has been shown to block a negative feedback loop, thereby leading to the activation of Akt. The activation of this Akt feedback loop has been suggested to potentially compromise the clinical efficacy of selective mTORC1 inhibitors such as temsirolimus and everolimus. Dual p70S6K/Akt inhibition may promote improved pathway inhibition and also block the negative consequences of Akt activation through the negative feedback loop. MSC2363318A is a highly selective, potent, adenosine triphosphate (ATP) competitive inhibitor of p70S6K, Akt1, and Akt3. In a cellular context, inhibition of p70S6K leads to potent inhibition of ribosomal protein S6 phosphorylation, while inhibition of Akt activity blocks the negative effects of a compensatory feedback loop. In addition, MSC2363318A exhibits potent anti-proliferative activity against many solid tumor cell lines in vitro, especially those with PI3K pathway genomic alterations. Further, MSC2363318A can also cross the blood-brain barrier (via pre-clinical studies in mice, rat, and dog), a unique characteristic that would allow for treating not only malignancies that are driven by PI3K pathway genomic alterations, but also indications with a high incidence of CNS metastases and primary malignancies of the central nervous system. Patient Derived Xenograft (PDX) models from breast cancers with a high prevalence of PI3K pathway genomic alterations; including, triple negative breast cancer and Her2+ breast cancer were evaluated. In addition, combinations with standard of care agents were then evaluated in these breast cancer PDX models. Results from these studies were correlated with PI3K pathway genomic modifications, and will be used to guide subsequent clinical studies. Citation Format: Bayard R. Huck, H Tian, Sakeena Syed, Jing Lin, Jianguo Ma, Anderson Clark, Remiguisz Kaleta, Andreas Machl, Erik Wilker, Marc Lecomte. Evaluation of p70S6K/Akt inhibitor MSC2363318A in patient derived xenograft (PDX) models of breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4516. doi:10.1158/1538-7445.AM2014-4516

Abstract A162: Identification of brain penetrant p70S6K/Akt inhibitor MSC2363318A.

The PI3K pathway is involved in the regulation of cell growth, proliferation, metabolism and other functions. Aberrant signaling (PTEN loss of function, PIK3CA mutation, Akt amplification, etc.) from the PI3K pathway is observed in >50% of all tumors. Clinical evidence suggests that inhibiting the PI3K pathway is beneficial for the treatment of solid tumors and tumors of the hematopoietic system. Inhibition of p70S6K via rapalogs has been shown to block a negative feedback loop, thereby leading to the activation of Akt. The activation of this Akt feedback loop has been suggested to potentially compromise the clinical efficacy of selective mTORC1 inhibitors such as temsirolimus and everolimus. Dual p70S6K/Akt inhibition may promote improved pathway inhibition and also block the negative consequences of Akt activation through the negative feedback loop.nnMSC2363318A is a highly kinase-selective, potent, adenosine triphosphate (ATP) competitive inhibitor of p70S6K, Akt1, and Akt3. In a cellular context, inhibition of p70S6K leads to potent inhibition of ribosomal protein S6 phosphorylation, while inhibition of Akt activity blocks the negative effects of a compensatory feedback loop. In addition, MSC2363318A exhibits potent anti-proliferative activity against many solid tumor cell lines in vitro, especially those with PI3K pathway genomic alterations. Further, MSC2363318A can also cross the blood-brain barrier, a unique characteristic that would allow for treating not only primary malignancies that are driven by PI3K pathway genomic alterations, but also indications with a high incidence of CNS metastases and primary malignancies of the central nervous system.nnOral treatment of mice with MSC2363318A resulted in significant inhibition of tumor growth in several subcutaneous human cancer xenograft models representing breast, pancreatic, glioblastoma and ovarian cancers. Of note, a breast cancer model possessing a PTEN loss of function showed tumor regression upon treatment with MSC2363318A. In addition, MSC2363318A exhibited increased exposure in tumors as compared to plasma, resulting in sustained inhibition of S6K phosphorylation for up to 24 hours. Key preclinical activities are being completed and first in human clinical studies are scheduled to be initiated in 2013.nnCitation Information: Mol Cancer Ther 2013;12(11 Suppl):A162.nnCitation Format: Bayard R. Huck, Andreas Machl, Erik Wilker, Hui Tian, Sakeena Syed, Jing Lin, Jianguo Ma, Anderson Clark, Roseann Waterhouse, Remiguisz Kaleta, Alina Micu, Lynne Soughley, Long Li, Karin Groll, Sonja Kroesser, Frank Beier, Ursula Hering, Marc Lecomte, Katrin Wichert, Mauro DAntonio, Paolo Di Eugenio. Identification of brain penetrant p70S6K/Akt inhibitor MSC2363318A. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A162.