Discovery of (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant Mutations

Abstract

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.

ALK Mutations Confer Differential Oncogenic Activation and Sensitivity to ALK Inhibition Therapy in Neuroblastoma

“…One new inhibitor, called ceritinib, was recently shown to inhibit ALK variants with crizotinib-resistant L1196M, or I1171T mutations (Friboulet et al, 2014), but not to overcome resistance of an F1174 mutation. Other inhibitors are also known to have differential effects on crizotinib-resistance mutations acquired in ALK -rearranged lung cancers (Johnson et al, 2014; Sakamoto et al, 2011). The data in Table 3 suggest that neuroblastoma patients with ALK-activating M1166R, I1170N/S or F1245 mutations should respond to crizotinib just as well as R1275Q-mutated patients.…”

Updated Evidence on the Mechanisms of Resistance to ALK Inhibitors and Strategies to Overcome Such Resistance: Clinical and Preclinical Data

“…Very importantly, both alectinib and ceritinib have been shown to be effective for crizotinib-resistant patients, with response rates of 55 and 56%, respectively [15,16]. In addition to these agents, several ALK inhibitors, such as AP26133, ASP3062, X-396, and PF-06463922, are currently under evaluation [23,24,25,26]. However, at present, it remains to be elucidated which inhibitor would achieve the longest PFS as a first-line ALK inhibitor, and on-going phase III trials, such as the ALEX study comparing alectinib with crizotinib, will clarify whether next-generation ALK inhibitors are superior to crizotinib or not.…”

“…In fact, this mutation was shown to induce resistance to alectinib and ceritinib in patients [33,36]. Intriguingly, AP26113 and PF-06463922 were reported to harbor anti-tumor activity in cells with the G1202R mutation, demonstrating the possible use of these inhibitors after failure of crizotinib, alectinib, and ceritinib through G1202R [26,50]. In addition, resistance to crizotinib by mutations at codons 1171 and 1174 may not be overcome by alectinib and ceritinib, respectively, given the findings that these mutations confer resistance to alectinib and ceritinib [32,34,35,36].…”

The next-generation ALK inhibitors

“…This compound seems to retain its signal-blocking effects even when several ALK mutations, leading to crizotinib resistance, are present [25]. Results of an ongoing phase I trial are pending.…”