Bridging academic science and clinical research in the search for novel targeted anti-cancer agents

Abstract

This review starts with a brief history of drug discovery & development, and the place of Asia in this worldwide effort discussed. The conditions and constraints of a successful translational R&D involving academic basic research and clinical research are discussed and the Singapore model for pursuit of open R&D described. The importance of well-characterized, validated drug targets for the search for novel targeted anti-cancer agents is emphasized, as well as a structured, high quality translational R&D. Furthermore, the characteristics of an attractive preclinical development drug candidate are discussed laying the foundation of a successful preclinical development. The most frequent sources of failures are described and risk management at every stage is highly recommended. Organizational factors are also considered to play an important role. The factors to consider before starting a new drug discovery & development project are described, and an example is given of a successful clinical project that has had its roots in local universities and was carried through preclinical development into phase I clinical trials.

Keywords: Drug discovery; drug development; targeted anti-cancer agents; translational R&D.

Figure 1

The flow of activities from a validated drug target to discovery (done at ETC) and early development (done at D3). Each phase is comprising several stages. Discovery of small molecular weight compounds usually proceeds from assay development and screening to hit-to-lead and then to the lead optimization phase. In early development we distinguish preclinical development with up scaling and GMP quality manufacturing, formulation, stability, GLP tox and ADME profiling; in early clinical trials we usually have a phase Ia for tolerability and pharmacokinetics; in phase Ib we often see an expansion phase where patient populations are enriched with patients who are likely to respond based on genomics data. GCP, Good Clinical Practice; MTD, Maximally tolerated dose; GMP, Good Manufacturing Practice; PDC, Preclinical Development Candidate; GLP, Good Laboratory Practice; PoC, Proof-of-Concept; DLT, Dose-limiting toxicity; ADME, Absorption, Distribution, Metabolism, Excretion.

Figure 2

Matrix organization.

Figure 3

The screening cascade of a typical project pursuing a small molecular weight compound-based approach. FBS, fragment-based screen; HTS, high-throughput screening; PK/PD, pharmacokinetics/pharmacodynamics; PDC, preclinical development candidate.

Figure 4

STF3A cells.

Figure 5

ETC-159 (phase I clinical trial, June 2015).