本帖最后由 老马 于 2015-3-20 19:39 编辑
AACR Annual Meeting 2015
Abstract Number: 2827
Presentation Title: Discovery of AP26113, a potent, orally active inhibitor of anaplastic lymphoma kinase and clinically relevant mutants
Presentation Time: Monday, Apr 20, 2015, 3:05 PM - 3:20 PM
Location: Room 113, Pennsylvania Convention Center
Author Block: Wei-Sheng Huang, Feng Li, Lisi Cai, Yongjin Xu, Sen Zhang, Scott D. Wardwell, Yaoyu Ning, Anna Kohlmann, Tianjun Zhou, Emily Y. Ye, Xiaotian Zhu, Narayana I. Narasimhan, Tim Clackson, Victor M. Rivera, David Dalgarno, William C. Shakespeare. ARIAD Pharmaceuticals, Inc., Cambridge, MA
Abstract Body: Phosphorus, despite its abundance in the human body, is rarely found in drug molecules, with clinical utility limited to a few phosphonic or bisphosponic acid-based medicines and several phosphonate or phosphate-containing prodrugs. Concerns about poor cell penetration, low oral bioavailability, or biological instability have limited application of these functional classes in drug design. In our efforts to discover pharmaceuticals with novel functionality, we introduced a neutral, stable phosphine oxide moiety as a unique hydrogen-bond acceptor in the design of anaplastic lymphoma kinase (ALK) inhibitors. ALK is a receptor tyrosine kinase first identified as a chromosomal rearrangement (NPM-ALK fusion gene) in anaplastic large cell lymphoma (ALCL) and subsequently detected as an alternate fusion oncogene (EML4-ALK) in a subset of non-small cell lung cancers (NSCLC). Crizotinib, the first approved ALK inhibitor, has demonstrated impressive clinical benefit in EML4-ALK (ALK+) NSCLC patients. Drug resistance, however, emerges rapidly and point mutations within the kinase domain have been identified as a major resistance mechanism. With the specific objective to identify more potent ALK inhibitors with pan-inhibitory activity against crizotinib-resistant ALK mutants, we designed and tested a series of phosphine oxide-based compounds culminating in the identification of the clinical candidate AP26113. AP26113 exhibited 10-fold greater potency than crizotinib against ALK-positive ALCL and NSCLC cell lines, and effectively inhibited clinically relevant crizotinib-resistant mutants. AP26113 displayed ~100-fold increased selectivity for ALK-positive cells over ALK-negative cell lines while maintaining selectivity over insulin receptor tyrosine kinase receptors. Consistent with the in vitro profile, AP26113 demonstrated oral efficacy in multiple ALK+ mouse models including Karpas-299 (ALCL), H3122 (NSCLC), and Ba/F3 cells expressing crizotinib resistant mutants including G1269S and L1196M. Finally, AP26113 exhibited excellent drug-like properties including high cell permeability and solubility, moderate cross-species protein binding, and inactivity toward major cytochrome P450 iso-enzymes and hERG ion channels. Medicinal chemistry efforts leading to the discovery of this potent pan-ALK inhibitor, including design strategy, chemical series evolution, and DMPK optimization will be presented. AP26113 is currently in a global phase 2 registration trial (NCT02094573) in patients with locally advanced or metastatic NSCLC who test positive for the ALK oncogene and were previously treated with crizotinib.
Abstract Number: 781
Presentation Title: The potent ALK inhibitor AP26113 can overcome mechanisms of resistance to first- and second-generation ALK TKIs in preclinical models
Presentation Time: Sunday, Apr 19, 2015, 1:00 PM - 5:00 PM
Location: Section 32
Poster Board Number: 13
Author Block: Sen Zhang, Sara Nadworny, Scott D. Wardwell, Lindsey Eichinger, Biplab Das, Emily Y. Ye, J. Graeme Hodgson, Victor M. Rivera. ARIAD Pharmaceuticals, Inc., Cambridge, MA
Abstract Body: Background:
Disease progression in anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) patients (pts) treated with the first-generation tyrosine kinase inhibitor (TKI) crizotinib, or the second-generation inhibitors ceritinib and alectinib, is often associated with secondary resistance mutations in ALK (such as G1202R, linked with resistance to all 3 TKIs in pts), or relapse in the brain. AP26113 is a highly potent ALK inhibitor with promising anti-tumor activity in pts with crizotinib-resistant disease. Here we broadly evaluate AP26113’s ability to overcome mechanisms of resistance to first- and second-generation ALK inhibitors, in preclinical models (including brain cancer models), and describe a novel methodology to compare in vitro potency, clinical pharmacokinetic parameters, and clinical efficacy.
Methods:
Ba/F3 cells were engineered to express native EML4-ALK or 17 mutants resistant to crizotinib, ceritinib, and/or alectinib in clinical or preclinical studies. IC50s for all TKIs were compared to “clinically effective” plasma concentrations (Ceff) of each inhibitor, which were derived using average steady-state levels in pts, and corrected for the functional effects of protein binding in vitro. In vivo studies were performed in mice, in which Ba/F3 cells with mutant or native EML4-ALK were injected subcutaneously, or a NSCLC line with EML4-ALK (H2228) was injected into the brain.
Results:
The Ceff of crizotinib was only ~2-fold above the IC50 for native ALK, suggesting that crizotinib may be susceptible to mutants that inhibit binding by only a few-fold. Indeed, 8/10 mutants previously associated with clinical resistance to crizotinib were found to have IC50s that exceed the Ceff. Similar analyses revealed mutants with IC50s that exceeded the Ceff for ceritinib (e.g. L1198F) and alectinib (e.g. I1171N), with G1202R being the most recalcitrant mutant overall. In contrast, the Ceff of AP26113 was >20-fold above the IC50 for native ALK, and exceeded the IC50 for all 17 mutants, including G2102R. In vivo, among all 4 TKIs tested (at doses effective against native ALK), only AP26113 demonstrated significant efficacy against G1202R-mutant ALK (88% tumor growth inhibition). Finally, compared to crizotinib, AP26113 markedly enhanced survival of mice bearing brain tumors.
Conclusion:
AP26113 inhibits all 17 clinically and preclinically observed crizotinib-, ceritinib-, and/or alectinib-resistant ALK mutants tested in vitro, has potent effects on the recalcitrant G1202R mutant in vivo and has activity in an orthotopic brain model. These results suggest AP26113 may effectively address a broad range of resistance mechanisms identified for other ALK TKIs. AP26113 is currently in a global phase 2 registration trial in patients with locally advanced or metastatic ALK+ NSCLC who were previously treated with crizotinib (NCT02094573).
重点翻译：AP26113在EML4-ALK的细胞株Ba/F3实验结果显示，它对17种alk突变均有良好抑制效果，包括L1196M 突变（crizotinib的耐药突变），L1198F突变（ceritinib的耐药突变），I1171N（alectinib的耐药突变），G1202R突变（crizotinib、ceritinib、alectinib的耐药突变）。 |
显身卡
