Small molecule cancer drug discovery and development has been evolving over the last decade to focus on personalized medicine, which emphasizes molecularly targeted drugs that exploit the particular genetic addictions, dependencies, and vulnerabilities of cancer cells.1

  • Small molecule drug targets are increasingly being revealed by the expanding understanding of the abnormal biology and genetics of cancer cells.1


  1. Target validation and selection: The selection of a new target for cancer drug discovery is increasingly based on the strength of evidence that the target represents a dependence or vulnerability for a given tumor type or subset of cancer patients; patients are commonly defined by their molecular genetic status.1
  2. Hit and lead generation: In general, there are two overall types of approaches for hit finding: knowledge-based design and random screening. Designing hits requires prior knowledge of the target structure and biology. In contrast, random screening does not require prior knowledge of target structure or of the inhibitors/ligands and involves the screening of large compound collections.1
  3. Lead optimization to select a clinical candidate: The optimization of a lead structure requires iterative rounds of medicinal chemistry design, synthesis, and multi-parameter testing. Once a preclinical candidate has been identified, sufficient preclinical data must be generated to support a clinical trial.1
  4. Biology-led clinical trials of targeted drugs: In the current targeted-therapy environment, clinical trials should be led by the biology and the clinical hypothesis, potentially allowing for biomarkers to drive the clinical trials.1

Therapeutic Potential

  • Small molecule drugs are able to pass across cell membranes and reach targets in the cell.2
  • Scientists have created a variety of small molecules ranging from enzyme inhibitors to compounds that block the interactions of critical proteins involved in tumor progression.
  • Pharmacological research in this area often focuses on approaches to restore the cancer cell's ability to die, including the BET family:
    • The BET family (BRD2, BRD3, BRD4, and BRDT) are bromodomain-containing proteins that interact with acetylated histone tails and play important roles in transcription regulation; inhibition of BET has been shown to induce apoptosis.3,4

Relevant Targets

  1. Hoelder S, et al. Discovery of small molecule cancer drugs: successes, challenges and opportunities. Mol Oncol. 2012;6(2):155-76.
  2. Yang NJ, Hinner MJ. Getting across the cell membrane: an overview for small molecules, peptides, and proteins. Methods Mol Biol. 2015;1266:29–53.
  3. Xu Y, Vakoc CR. Targeting cancer cells with BET bromodomain inhibitors. Cold Spring Harb Perspect Med. 2017;7(7).
  4. Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904-917.