How Small Molecules are Advancing Treatments

Part II: Hepatitis C, Cancer, and Diabetes
Patients with hepatitis C, cancer, or diabetes are living longer with higher qualities of life thanks in part to advancements in target small molecule therapy.

Hepatitis C
Hepatitis C (HCV) was first identified and is believed to account for 90% to 95% of cases scientists had previously labeled non-A and non-B hepatitis.131 Interferon, so named because it interferes with viral replication, was the first class of treatments approved for HCV. Approved in 1991, interferon alpha, was first to market to treat HCV.132 Combination therapies with interferons and antiviral medications ushered in the next generation of therapies.133 Interferons are large polypeptides typically weighing 16 kDa to 20 kDa.

Recently, several new classes of small molecule hepatitis C drugs targeting different viral enzymes/reproduction mechanisms have emerged.134,135 These compounds have revolutionized care, by producing cures (undetectable viral load) in a large proportion (>80%) of both naive and experienced patients. The following drugs are indicated for the treatment of hepatitis C:

  • Sofosbuvir, (nucleotide analog NS5B polymerase inhibitor; genotypes 1,2,3,4);
  • Daclatasvir (NS5a replication complex inhibitor/sofosbuvir; genotype 3);
  • Ombitasvir/paritaprevir/ritonavir combination (NS5a replication complex inhibitor/NS3/4a protease inhibitor/CYP3A inhibitor; genotype 4);
  • Ledipasvir/sofosbuvir combination (NS5a inhibitor/NS5b polymerase inhibitor; genotype 1)
  • Simeprevir (NS3/4a protease inhibitor; genotype 1)

For centuries, excision was the only available treatment for cancer.136 The influence of hormones on tumor growth formed the basis of small molecule treatments such as tamoxifen and aromatase inhibitors. Chemotherapy with small molecules revolutionized cancer treatment by killing tumor cells that were not removed via surgery or eradicated by radiation, and thereby enabling long-term remission.137 Increased understanding of genetic differences in tumors and people has led to personalized cancer treatments.138 Genetic traits of the tumor can be profiled to determine its susceptibility to a drug (e.g., BCR- ABL translocation, EGFR mutation for example). A profile can also determine a person’s individual ability to metabolize a drug (e.g., CYP450 enzymes, UGT1a1, DPYD), which can impact exposure, efficacy, and side effects.139,140

The class of therapies known as growth signal inhibitors comprises small molecules that block tumor growth signals and represent a leap forward in oncology treatment. Gefitinib and imatinib are two widely prescribed small molecule growth signal inhibitors.141 The American Society of Clinical Oncology (ASCO) calls the development of imatinib one of the top 5 advances in modern oncology.142 FDA approval of imatinib for chronic myelogenous leukemia launched a new era of oncology drugs that target a cancer cell’s specific molecular defects, but spare surrounding healthy tissue.143

Traditional treatment for diabetes includes exogenous insulin taken in formulations that attempt to mimic normal endogenous pancreatic secretion. Sulfonylureas, small molecules that stimulate the pancreas to release more insulin, also treat diabetes. They have been introduced in two waves: first in the 1950s and then again in the 1980s. The latter medications enabled patients to take smaller doses and reportedly have fewer treatment-related adverse events.144 Newer small molecules enhance the body’s own ability to lower elevated blood sugar (e.g., DPP-4 inhibitors) or block the activity of sodium glucose transport in the kidneys (e.g., canagliflozin, dapagliflozin).145,146

While some new classes of therapies to treat diabetes include large polypeptides (e.g., GLP-1 inhibitors) an orally active small molecule, AdipoRon, has shown promising preclinical results. AdipoRon ameliorates diabetes in genetically obese rodent models.147

Small molecules have revolutionized the treatment of HCV, cancer, and diabetes. Whereas HCV was formerly a chronic and debilitating condition, small molecules have enabled cures. Oncology treatments have evolved dramatically over the last few decades. Targeted, and personalized small molecule therapies have ushered in a new era in cancer treatment. Finally, diabetes treatments typically involve peptides (e.g., insulin), however, new orally available small molecules act through a variety of mechanisms and often supplement insulin therapy making it more effective. Across these three disease states, the development of small molecule based therapies has led to increased survival, and quality of life in many patients.