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  • Review Article
  • Published:

Discovery and development of sorafenib: a multikinase inhibitor for treating cancer

Nature Reviews Drug Discovery volume 5, pages 835–844 (2006)Cite this article

A Corrigendum to this article was published on 01 February 2007

Key Points

  • Increased understanding of the molecular basis of cancer since the 1980s has shifted the focus of drug discovery and development away from non-specific chemotherapeutics and towards rationally designed drugs that target cancer-specific pathways.

  • The Raf serine/threonine kinase isoforms (A-Raf, B-Raf and Raf1(or C-Raf)) are the first kinases in the MAPK cascade and are pivotal regulators of cellular proliferation and survival.

  • In 1989, it was shown that disrupting the raf1 gene using the specific antisense oligonucleotide (ASON) ISIS 5132 inhibits the growth of human lung, breast and ovarian tumour xenografts in athymic mice, providing the first proof-of-concept that the raf1 gene is a valid anticancer target.

  • By 1994, Bayer and Onyx had engaged in a collaboration to discover novel therapies targeting the RAS–RAF–MEK–ERK pathway. HTS screening for Raf1 kinase inhibitory activity was initiated in 1995, and identified a promising lead compound that was subsequently optimized by medicinal chemistry efforts to give sorafenib.

  • Sorafenib directly blocks the autophosphorylation of several receptor tyrosine kinases (RTKs) —VEGFR1, 2 and3, PDGFRβ, c-Kit and RET — as well as inhibiting downstream Raf kinase isoforms in cell lines. The targeting of several RTKs involved in angiogenesis (VEGFR1, 2, 3 and PDGFRβ) and tumorigenesis (Flt-3, c-Kit and RET) might be responsible for its broad-spectrum activity in several models of human cancer.

  • As the molecular targets of sorafenib are involved in the aetiology of many common malignancies, it was first evaluated in a mixed population of patients with several forms of advanced solid tumours.

  • On the basis of the promising preliminary activity in renal cell carcinoma (RCC) patients across the Phase I trials, Bayer and Onyx decided to evaluate sorafenib monotherapy as a treatment for RCC by enriching the recruitment of RCC in an accruing Phase II trial, with a randomized discontinuation trial design.

  • The very high rate of RCC patients who were progression-free after 12 weeks of dosing in this Phase II trial led to the initiation of the Phase III study to assess the safety and activity of sorafenib.

  • These two randomized controlled trials confirmed sorafenib's activity against RCC by showing that it significantly prolonged progression-free survival (PFS) compared with placebo in patients with advanced disease

  • The Phase II/III results established oral sorafenib (400 mg bid) as a safe and effective new treatment for metastatic RCC and formed the basis for its FDA marketing approval in December 2005 for the treatment of advanced RCC.

  • Future issues for the development of sorafenib include the identification and validation of appropriate biomarkers for improved patient selection, prognostication and/or as response endpoints.

Abstract

Since the molecular revolution of the 1980s, knowledge of the aetiology of cancer has increased considerably, which has led to the discovery and development of targeted therapies tailored to inhibit cancer-specific pathways. The introduction and refinement of rapid, high-throughput screening technologies over the past decade has greatly facilitated this targeted discovery and development process. Here, we describe the discovery and continuing development of sorafenib (previously known as BAY 43-9006), the first oral multikinase inhibitor that targets Raf and affects tumour signalling and the tumour vasculature. The discovery cycle of sorafenib (Nexavar; Bayer Pharmaceuticals) — from initial screening for a lead compound to FDA approval for the treatment of advanced renal cell carcinoma in December 2005 — was completed in just 11 years, with approval being received ∼5 years after the initiation of the first Phase I trial.

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Figure 1: Summary of the chemical optimization of sorafenib.
Figure 2: Cellular targets of sorafenib.
Figure 3: Clinical activity of sorafenib in cancer efficacy trials.

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  1. Department of Cancer Research, Bayer Pharmaceuticals Corp., West Haven, 06516, Connecticut, USA

    Scott Wilhelm, Christopher Carter, Mark Lynch, Timothy Lowinger, Jacques Dumas, Roger A. Smith, Brian Schwartz, Ronit Simantov & Susan Kelley

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FURTHER INFORMATION

Nexavar

Glossary

Metastasis

The spread of cancer cells through lymphatics/blood vessels to other sites or tissues in the body (for example, brain or liver).

Epigenetic events

Reversible heritable changes in gene function or other cell phenotype that occur without a change in DNA sequence.

Therapeutic Index

(Also known as therapeutic ratio or margin of safety). A comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxic effects.

Scintillation proximity assay (SPA)

A process that uses fluoromicrospheres coated with streptavidin to detect phosphorylation of substrates by kinases, which has become an important technique in high-throughput screening (HTS) for new drugs.

Xenograft

Xenograft mouse models of cancer are created by injecting homogeneous human tumour cell lines into immunodeficient mice.

Combinatorial chemistry

Any of various technologies for the rapid synthesis of large collections of compounds to facilitate the identification of new active compounds for drug targets by high-throughput screening techniques.

IC50

The half maximal inhibitory concentration, or the concentration of an inhibitor that is required for 50% inhibition of a biochemical or cellular target.

Angiogenesis

The growth of new blood vessels from pre-existing vessels. Angiogenesis is a normal process in growth and development but is also a fundamental process required for the growth of tumours.

Pericytes

Elongated contractile cells found in association with arterioles outside the basement membrane.

Apoptosis

Programmed cell death.

RECIST criteria

Response Evaluation Criteria in Solid Tumors are standardized, radiographic criteria for determining tumour response or progression in clinical trials of cancer drugs.

Randomized discontinuation trial (RDT) design

A two-phase trial: in Phase I all patients are openly treated with the medication being evaluated; in Phase II, those with stable disease are randomly assigned to continue the same treatment or switch to placebo.

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Wilhelm, S., Carter, C., Lynch, M. et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5, 835–844 (2006). https://doi.org/10.1038/nrd2130

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