The Discovery and Optimization of a Novel Class of Potent, Selective, and Orally Bioavailable Anaplastic Lymphoma Kinase (ALK) Inhibitors with Potential Utility for the Treatment of Cancer

Abstract

A class of 2-acyliminobenzimidazoles has been developed as potent and selective inhibitors of anaplastic lymphoma kinase (ALK). Structure based design facilitated the rapid development of structure-activity relationships (SAR) and the optimization of kinase selectivity. Introduction of an optimally placed polar substituent was key to solving issues of metabolic stability and led to the development of potent, selective, orally bioavailable ALK inhibitors. Compound 49 achieved substantial tumor regression in an NPM-ALK driven murine tumor xenograft model when dosed qd. Compounds 36 and 49 show favorable potency and PK characteristics in preclinical species indicative of suitability for further development.

Impact of Hydrolysis-Mediated Clearance on the Pharmacokinetics of Novel Anaplastic Lymphoma Kinase Inhibitors

“…Although this decrease in hydrolysis was attributed to steric hindrance, electronic effects may also be implicated since substantial decrease in hydrolysis may also be achieved by parasubstitution (Testa and Mayer, 2003). In the case of the ALK inhibitors described here, ortho-substitution was not tolerated, most likely due to the distortion of the coplanar conformation that was required for an optimum interaction with the ALK protein (Lewis et al, 2012). Studies of meta-or para-substitution on the benzamide moiety demonstrated a clear structure activity relationship.…”

“…All fresh plasma and blood were obtained from the in vivo group at Amgen. All proprietary ALK inhibitors were synthesized by the Department of Medicinal Chemistry at Amgen (Cambridge, MA) and all synthetic routes have already been published elsewhere (Lewis et al, 2012). All other chemicals were purchased from Sigma-Aldrich (Milwaukee, WI) unless otherwise specified Determination of Stability or CL int in Plasma.…”

“…imidazol-2(3H)-ylidene)benzamide], is a member of a new class of potent and selective ALK inhibitor with potential application in the treatment of cancer (Lewis et al, 2012). In vitro screening of compound 1 resulted in excellent inhibitory activity against the ALK enzyme (IC 50 = 1 nM) and ALK expressing Karpas-299 cells (4 nM) (Lewis et al, 2012).…”

“…In vitro screening of compound 1 resulted in excellent inhibitory activity against the ALK enzyme (IC 50 = 1 nM) and ALK expressing Karpas-299 cells (4 nM) (Lewis et al, 2012). Rat in vivo studies showed acceptable pharmacokinetics (PK) with a clearance (CL) of 0.8 l/h per kg, a half-life (t 1/2 ) of 5.6 hours, and mean residence time (MRT) of 8 hours (Lewis et al, 2012). Based on potency and preliminary rodent pharmacokinetics, compound 1 was selected as a candidate to advance into efficacy studies in mice.…”

The R1275Q Neuroblastoma Mutant and Certain ATP-competitive Inhibitors Stabilize Alternative Activation Loop Conformations of Anaplastic Lymphoma Kinase

“…The exception is CH5424802, which binds in a more linear fashion to the hinge region of ALK and extends further back into the pocket adjacent to gatekeeper residue Leu 1196 . Both types of inhibitors display exquisite potency on ALK and a third class of molecules combining elements of both of the first two classes produces another type of potent, selective ALK inhibitor (60). Importantly, the contour of the portion of the ATP site into which these inhibitors bind is not affected in the F1174L or R1275Q neuroblastoma mutants, as described above, nor is it expected to be perturbed upon ALK kinase domain phosphorylation.…”