Learning and Confirming with Preclinical Studies: Modeling and Simulation in the Discovery of GDC-0917, an Inhibitor of Apoptosis Proteins Antagonist

Abstract

The application of modeling and simulation techniques is increasingly common in the preclinical stages of the drug development process.is a potent second-generation antagonist of inhibitor of apoptosis (IAP) proteins that is being developed for the treatment of various cancers. GDC-0917 has low to moderate clearance in the mouse (12.0 ml/min/ kg), rat (27.0 ml/min/kg), and dog (15.3 ml/min/kg), and high clearance in the monkey (67.6 ml/min/kg). Accordingly, oral bioavailability was lowest in monkeys compared with other species. Based on our experience with a prototype molecule with similar structure, in vitroin vivo extrapolation was used to predict a moderate clearance (11.5 ml/min/kg) in humans. The predicted human volume of distribution was estimated using simple allometry at 6.69 l/kg. Translational pharmacokinetic-pharmacodynamic (PK-PD) analysis using results from MDA-MB-231-X1.1 breast cancer xenograft studies and predicted human pharmacokinetics suggests that ED 50 and ED 90 targets can be achieved in humans using acceptable doses (72 mg and 660 mg, respectively) and under an acceptable time frame. The relationship between GDC-0917 concentrations and pharmacodynamic response (cIAP1 degradation) was characterized using an in vitro peripheral blood mononuclear cell immunoassay. Simulations of human GDC-0917 plasma concentration-time profile and cIAP1 degradation at the 5-mg starting dose in the phase 1 clinical trial agreed well with observations. This work shows the importance of leveraging information from prototype molecules and illustrates how modeling and simulation can be used to add value to preclinical studies in the early stages of the drug development process.

Targeting the Inhibitor of Apoptosis Protein BIR3 Binding Domains

“…Several key proline amide caps include 1-(S)-amino-1,2,3,4-tetrahydronaphthene [30], diphenylmethylamino [27,31] and substituted heteroaromatic based amides [32,33]. The work by Genentech provided the clinical compounds GDC-0152 [34] and GDC-0917 [35]. GDC-0917 was licensed to Curis and renamed CUDC-427.…”

“…Binding to cIAP1 and cIAP2 induces E3 ubiquitin ligase activity resulting in ubiquination of RIPK1, canonical NF-κB activation, cIAP1 and cIAP2 autoubiquitination, and their subsequent proteasomal degradation [78,79]. Therefore, loss of cIAP1 protein from cellular lysates and clinical samples has served as an effective biomarker during both preclinical and clinical development [1][2][3][4][5][6][7][8]34,35,44,70,95,96,100,110]. As such, both singleagent and combination trials are ongoing.…”

Targeting apoptotic machinery as approach for anticancer therapy: Smac mimetics as anticancer agents

“…Actually, the development of peptidomimetic inhibitors of IAP with more favorable pharmacokinetic properties followed the following strategies: N-methylation of Ala residue (as in compounds 1 and 2) replacement of the 2 nd and 3 rd residues with nonnatural amino acids and capping of the C-terminal with aromatic group (in compound 1) and heteroaromatic group (in compound 2 and 3), where these hydrophobic groups extend in the hydrophobic pocket that was initially occupied with Ile residue in Smac tetrapeptide or Phe [22]. Compound 3 (GDC-0917) is a second generation Smac mimetic that enjoyed the advantage of oral dosing over compound 2 which is adminsterd intravenously 23 . …”

Smac-Derived Aza-Peptide As an Aminopeptidase-Resistant XIAP BIR3 Antagonist

“…It is worth mentioning here that only the N-terminally mono-methylated (N-methyl) Smacderived peptides have preserved IAP inhibitory activity [4], and the this modification is thus currently widely used as an aminopeptidase resistant residue at P1 in the Smac-derived peptidomimetic and in non-peptidic clinical candidates [11][12][13][14][15][16][17][18].…”

“…This is because of the innate and generally impaired bioavailability of peptide ligands mainly due to their instability towards proteolytic cleavage. There have been long standing efforts in developing protease-resistant Smac-derived peptidomimetics (monovalent and bivalent) and non-peptidic analogues by ourselves [3] and many other groups [4][5][6][7][8][9] that led in some cases to IAP inhibitors that reached clinical trials [10] such as LCL-161 [11,12], SM-406/AT-406 [13,14], GDC-0512/GDC-0917 [15,16], and birinapant [17,18], and thus are drug-like compounds with suitable efficacy, bioavailability and tolerability.…”