Targeted drug discovery for pediatric leukemia

Abstract

Despite dramatic advances in the treatment of pediatric leukemia over the past 50 years, there remain subsets of patients who respond poorly to treatment. Many of the high-risk cases of childhood leukemia with the poorest prognosis have been found to harbor specific genetic signatures, often resulting from chromosomal rearrangements. With increased understanding of the genetic and epigenetic makeup of high-risk pediatric leukemia has come the opportunity to develop targeted therapies that promise to be both more effective and less toxic than current chemotherapy. Of particular importance is an understanding of the interconnections between different targets within the same cancer, and observations of synergy between two different targeted therapies or between a targeted drug and conventional chemotherapy. It has become clear that many cancers are able to circumvent a single specific blockade, and pediatric leukemias are no exception in this regard. This review highlights the most promising approaches to new drugs and drug combinations for high-risk pediatric leukemia. Key biological evidence supporting selection of molecular targets is presented, together with a critical survey of recent progress toward the discovery, pre-clinical development, and clinical study of novel molecular therapeutics.

Keywords: drug discovery; lead optimization; leukemia; medicinal chemistry; molecular target; targeted therapy.

Figure 1

Pediatric leukemia survival trends from 1950 to the present. Data obtained from Kersey (1997) and Pui et al. (2011b).

Figure 2

Compounds targeting inhibition of cell proliferation or induction of apoptosis. Numbers in bold type are used to refer to compounds in this figure from the main text, Figure 4, and Table 1. (A) BCR-ABL inhibitors, (B) FLT3 inhibitors, (C) mTOR inhibitors, (D) AKT inhibitor, (E) JAK1/2 inhibitors, (F) aurora kinase inhibitors, (G) proteasome inhibitor, (H) BCL-2 antagonists.

Figure 3

Compounds targeting transcription or stem cell homing. Numbers in bold type are used to refer to compounds in this figure from the main text, Figure 5, and Table 1. (A) DNA methyltransferase inhibitors, (B) histone deacetylase inhibitors, (C) DOT1L inhibitors, (D) BRD4 inhibitors, (E) Menin-binding inhibitor, (F) CXCR4 antagonist.

Figure 4

Cell proliferation targets. Numerous interconnections between targets and other cellular proteins are omitted for clarity. Numbers in bold type refer to inhibitors shown inFigure 2.

Figure 5

Transcriptional targets. Numerous interconnections between targets and other proteins involved in transcriptional activation are omitted for clarity. HDAC, histone deacetylase; DNMT, DNA methyltransferase. Numbers in bold type refer to inhibitors shown inFigure 3.