talabostat and Neoplasms

The extent to which a drug inhibits a target responsible for a therapeutic effect is a more rational primary endpoint for dose-finding studies of more selective anticancer drugs than the conventional endpoint of dose-limiting toxicity (DLT) used for cytotoxic agents. An adaptive phase I trial design incorporating maximum target inhibition as the primary endpoint was developed to define the optimal dose of talabostat, a dipeptidyl peptidase (DPP) inhibitor, in children with relapsed or refractory solid tumors. The relationship between dose and effect (percent inhibition of serum DPP-4) was assessed using a maximum effect model. Maximum target inhibition was defined as greater than 90% DPP-4 inhibition in five or more of six patients 24 hours post-dose. If DLT was to occur, the trial would adapt to a traditional phase I design with a more conservative dose escalation. At the 600 microg/m(2) dose level, serum DPP-4 inhibition at 24 hours was 85%. No talabostat-related DLT occurred. The maximum effect model predicted that 1200 microg/m(2) of talabostat would maximally inhibit DPP-4. This adaptive trial design appears to be feasible, safe, and efficient and warrants further evaluation for development of molecularly targeted agents.

Topics: Administration, Oral; Adolescent; Antineoplastic Agents; Area Under Curve; Boronic Acids; Child; Child, Preschool; Confounding Factors, Epidemiologic; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Endopeptidases; Female; Gelatinases; Humans; Male; Membrane Proteins; Neoplasms; Research Design; Serine Endopeptidases

We have previously described several different chemical series of bicyclic prolyl oligopeptidase (POP) inhibitors as probes for neurodegenerative diseases that demonstrated nanomolar activity in vitro and submicromolar activity in cellulo. The more recent implication of POP in cancer, together with homologous fibroblast activation protein α (FAP), implicated in tumor growth, led us to consider developing POP/FAP dual inhibitors as a promising strategy for the development of cancer therapeutics. At this stage, we thought to evaluate the requirements for selectivity of inhibitors for POP over FAP and to evaluate molecular platforms that would enable the development of selective POP and dual POP/FAP inhibitors. We report herein docking-guided design of a new bicyclic scaffold and synthesis of both covalent and non-covalent bicyclic inhibitors. Biological evaluation of first-of-their-kind [4.3.0] bicyclic compounds confirmed that reactive groups, or covalent warheads, are required for inhibitor activity. This work ultimately led to one scaffold yielding new POP-selective inhibitors and a dual inhibitor equipotent to the only drug targeting FAP and POP that ever reached clinical trials.

Topics: Endopeptidases; Enzyme Inhibitors; Humans; Membrane Proteins; Neoplasms; Prolyl Oligopeptidases; Serine Endopeptidases