Small Molecules and Drug Discovery

Phases of drug discovery and development25
The process of small molecule drug discovery occurs over many years (10-20 or more) and in phases. From 1995 to 2007, 12.6% of compounds entering clinical trials were approved.26

Phases of Small Molecule Drug Discovery27

Phase Time Advancing to next phase (%) Capitalized R&D Costs
Target Identification Years N/A
Target Validation 1-2 years N/A 94 million USD28
Lead Identification (Hit-to-lead) 1-2 years ~0.1 166 million USD29
Lead Optimization ~2 years to 1st generation compounds ~0.002 414 million USD30
Preclinical Development Varies ~25% 150 million USD31
Total prior to Clinical entry~1.098 billion USD
Clinical Development Phase I           20 mo. 59% Varies
Phase II          30 mo. 35% Varies
Phase III         30 mo. 62% Total Clinical costs~1.46 billion USD
Total 6-7 years 3 phase success 12%
FDA Filing Total for all phases~2.56 billion USD

Target validation
Biologists and chemists demonstrate that interaction with the selected biological target leads to the desired biological effect during the target validation phase. Commercially available small molecules can help validate targets. Compounds with known mechanisms can be used as positive or negative controls32 in assay development, or as tools in counter screening to check for undesired properties.33

  • Common positive controls:
    • Geldanamycin: Regulates heat shock protein hsp90
    • LY 294002: PI3 kinase inhibitor
    • AG-1478: potent and selective EFGR kinase inhibitor
    • Lactacystin: specific chymotrypsin and trypsin inhibitor
  • Common tools for counter screening:
    • Dofetilide34, MK-49935 and E-403136: class III antiarrhythmic agents37 that selectively block the potassium current (Ikr) conducted by the hERG channel38
    • Astemizole: antihistamine that is also a hERG blocker
    • Nifedipine: L-type calcium channel blocker
    • Staurosporine: non-selective protein serine/threonine kinase inhibitor
    • Rolipram: selective PDE4 inhibitor

Lead identification (hit-to-lead)
Medicinal chemists search for novel molecules to develop into a marketable drug. Ideally this process investigates 2-3 distinct chemical structures to develop in parallel. Methods include:

  • Design and synthesis of novel chemical structures based on literature and patent precedent
  • High throughput and small scale screening of molecular libraries
  • Modeling and virtual library screening when X-ray information is available for the target

Through screening, active compounds (“hits”) are identified. From these “hits” high value “leads” are identified after confirmation of their structure through chemical re-synthesis and purification, and of their activity through biological characterization of the purified material.39

From high throughput screening of millions of compounds, ~10 to 100’s of hits may be identified and produce <20 confirmed, high value leads. These are narrowed to 2-3 lead series for lead optimization.40

Lead optimization
Project members seek an optimal balance of many desired properties in a single molecule. These properties include appropriate potency, selectivity, physical properties and in vivo activity. Teams of chemists often synthesize many analogs (1,000-10,000 or more) to achieve this balance. The expertise of many disciplines41 informs the choice of 1-2 compounds as pre-clinical candidates.42

Preclinical development
Preclinical testing and clinical development is costly, as it encompasses detailed safety profiling of the candidate compound and requires kilos of compound. Compounds often fail at this stage and must be replaced, which is why exploration of several distinct chemical series in the lead optimization stage is desirable.43

Clinical development44
Following preclinical trials, a drug candidate moves into clinical testing. Clinical trials determine the safety and efficacy of a drug.

  • Phase I: healthy human subjects, evaluate safety
  • Phase II: human disease subjects, small trials
  • Phase III: human disease subjects, expanded trials, co-dosing with other drugs
  • Phase IV: post approval by FDA, additional trials to monitor for long-term side effects

FDA filing
A New Drug Application (NDA) provides data to support that the drug’s proposed use is safe, and that it is appropriately labeled and can be produced with high quality.45

From One-Size-Fits-All to Precision Medicine
The choice of the correct target is extremely important to the success of the project.  Genetic profiling has opened up many new targets for exploration. In oncology, this has revolutionized small molecule drug discovery.46

In the past, anti-cancer drugs like mitomycin C and doxorubicin (DNA interchelators) interacted with both cancer and normal cells. These broad spectrum drugs relied on the faster rate of growth in cancer cells to differentiate them from normal cells. In the last decade, drugs have been developed using genetic profiles of cancer cells. These profiles can reveal cell mechanisms resulting from genetic mutations that differentiate the cancer cells from normal cells.47

Examples of small molecule drugs that have been developed in the past decade and their anti-cancer indications include48:

  • All-trans retinoic acid – acute pro-myelocytic leukemia49
  • Imatinib ─ myeloid leukemia50
  • Gefitinib, erlotinib – non-small cell lunch cancer51
  • Lapatinib – ERBB2-positive breast cancer52
  • Sorafenib – renal cancer53
  • Abiraterone – castration resistant prostate cancer54
  • Crizotinib ─ non-small cell carcinoma crizotinib55
  • Vemurafenib – metastatic melanoma56

The pathway from small molecule to drug discovery and development progresses through many stages often over the course of a decade or more. The odds of a single compound becoming a marketed therapy are very small. Phases of the drug discovery and development process focus on identification and optimization of a potential therapy. Preclinical and clinical trial phases assess safety and efficacy of a proposed therapy before regulatory approval.