SUGEN

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SUGEN (Sugen) was a drug discovery company focused on development of protein kinase inhibitors. It was founded in 1991, and shut down in 2003, after pioneering protein kinases as therapeutic targets and developing the successful cancer therapy sunitinib (Sutent).

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Early history and focus

Sugen was founded in 1991 in Redwood City, California, by veteran biotech investor Stephen Evans-Freke and kinase researchers Joseph Schlessinger and Axel Ullrich. The name was derived from the initials of Schlessinger and Ullrich, and the "GEN" for Genetics. Sugen developed small-molecule inhibitors of protein kinases, key enzymes in signal transduction and cellular decision-making. The main focus was on oncology, though the company had collaborations in other therapeutic areas. The concept of inhibiting kinases by small molecules that mimicked the ATP structure was generally thought to be infeasible when the company was founded (due to the high (mM) concentration of ATP in cells), and Sugen has been credited with pioneering this area, [1] leading to protein kinases being the second most active area of drug development, largely based on ATP-competitive inhibitors. Sugen also had research programs on protein phosphatases, none of which led to therapeutics.

Research and drug development

Sugen went public in October 1994 (NASDAQ: SUGN). [2] In 1997, it filed its first Investigational New Drug (IND) application, for a PDGFR inhibitor, SU101. [3] This failed clinically, but was followed by a different series of compounds [4] that inhibited VEGFR kinases (involved in angiogenesis) as well as PDGFR and Kit. Of these, SU5416 (Semaxanib) and SU6668 went into clinical trials for colon cancer in 1999. SU5416 proceeded to Phase 3 trials, while the follow-on compound, SU11248 (Sunitinib) was later approved for human use, and a related compound SU11654 (Toceranib) was approved for canine tumors.

Sugen was funded through a number of collaborative research programs with companies including ASTA Medica (pan-Her and Raf programs), Allergan (ophthalmic angiogenesis inhibition), Zeneca (EGFR and cancer), and Amgen all of which took equity stakes in the company, [5] and Taiho (cancer). [6] Conversely, Sugen was an investor in and collaborator with Selectide for the development of peptide kinase inhibitors. [7]

Mergers

Sugen was acquired by Pharmacia & Upjohn in 1999 in a stock swap valued at $650 million. [8] In December 1999, Pharmacia & Upjohn merged with Monsanto. [9] The company was renamed Pharmacia in 2002. [10] Pharmacia was then acquired by Pfizer in April 2003. [11]

Shutdown and legacy

The Pfizer-Pharmacia merger lead to major cuts in research activities, including the shut down of Sugen over the course of 2003, with the loss of approximately 350 employees. [1] Pfizer continued the phase 3 trials and development of SU11248, now known as Sutent (sunitinib), [4] leading to Food and Drug Administration approval in January 2006 for treatment of RCC and GIST tumors. Other programs also transferred to Pfizer, including a follow-on compound to SU11248, known as SU14813, and programs on Met and PAK kinases. Work started at Sugen also contributed to the development of the ALK inhibitor crizotinib (Xalkori), FDA-approved for NSCLC in 2011. [12] [13] Sugen also generated extensive basic research on kinase biology, including the publication of almost 300 research papers, [1] the definition of the human kinome, and the discovery of over 140 human kinase genes. Sugen alumni have gone on to major positions [14] in other pharmaceutical and kinase-focused companies. In 2010, Sutent surpassed $1bn in annual revenues for Pfizer. [15] [16]

Related Research Articles

Tyrosine kinase Class of enzymes that phosphorylate protein tyrosine residues

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.

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Pharmacia & Upjohn

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G.D. Searle, LLC is a wholly owned trademark of Pfizer. It is currently used mainly as a distribution trademark for various pharmaceuticals that were developed by G. D. Searle & Company. Prior to its 1985 merger with Monsanto, Searle was a company focusing on life sciences, specifically pharmaceuticals, agriculture, and animal health.

Epirubicin

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Targeted therapy

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Sunitinib Cancer medication

Sunitinib is an oral, small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST) on January 26, 2006. Sunitinib was the first cancer drug simultaneously approved for two different indications.

Axel Ullrich is a German cancer researcher and has been the director of the molecular biology department at the Max Planck Institute of Biochemistry in Martinsried, Germany since 1988. This department's research has primarily focused on signal transduction. Ullrich has received Hamdan Award for Medical Research Excellence, awarded by Sheikh Hamdan bin Rashid Al Maktoum Award for Medical Sciences, Dubai, United Arab Emirates in 2008 and Ullrich and his team received the Wolf Prize in 2010.

Semaxanib

Semaxanib (SU5416) is a tyrosine-kinase inhibitor drug designed by SUGEN as a cancer therapeutic. It is an experimental stage drug, not licensed for use on human patients outside clinical trials. Semaxanib is a potent and selective synthetic inhibitor of the Flk-1/KDR vascular endothelial growth factor (VEGF) receptor tyrosine kinase. It targets the VEGF pathway, and both in vivo and in vitro studies have demonstrated antiangiogenic potential.

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Toceranib

Toceranib is a receptor tyrosine kinase inhibitor and is used in the treatment of canine mast cell tumor also called mastocytoma. Together with masitinib, toceranib is the only dog-specific anti-cancer drug approved by the U.S. Food and Drug Administration. It is marketed as Palladia as its phosphate salt, toceranib phosphate (INN) by Pfizer. It was developed by SUGEN as SU11654, a sister compound to sunitinib, which was later approved for human therapies. Toceranib is likely to act mostly through inhibition of the kit tyrosine kinase, though it may also have an anti-angiogenic effect.

SU6656

SU6656 is a Src family kinase inhibitor developed by the biotechnology company SUGEN Inc in 2000. SU6656 was initially identified as a Src kinase inhibitor by virtue of its ability to reverse an effect that an activated mutant form of Src has on the actin cytoskeleton, namely the formation of podosome rosettes, otherwise known as invadopodia. SU6656 was initially published as a Src family kinase inhibitor with selectivity relative to Platelet-derived growth factor receptor Tyrosine kinase. Subsequent studies have confirmed that SU6656 is relatively selective for Src family kinases but some additional biochemical activities have been identified including: BRSK2, AMPK, Aurora C, Aurora B, CaMKKβ. The inhibition of these kinases in biochemical reactions in vitro does not necessarily indicate that these kinases are targets of SU6656 in cells.

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Crizotinib

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Crenolanib

Crenolanib besylate is an investigational inhibitor being developed by AROG Pharmaceuticals, LLC. The compound is currently being evaluated for safety and efficacy in clinical trials for various types of cancer, including acute myeloid leukemia (AML), gastrointestinal stromal tumor (GIST), and glioma. Crenolanib is an orally bioavailable benzamidazole that selectively and potently inhibits signaling of wild-type and mutant isoforms of class III receptor tyrosine kinases (RTK) FLT3, PDGFR α, and PDGFR β. Unlike most RTK inhibitors, crenolanib is a type I mutant-specific inhibitor that preferentially binds to phosphorylated active kinases with the ‘DFG in’ conformation motif.

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Ceritinib

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References

  1. 1 2 3 Garber, Ken (16 July 2003). "Research Retreat: Pfizer Eliminates Sugen, Shrinks Cancer Infrastructure (subscription required)". JNCI: Journal of the National Cancer Institute. 95: 1036–1038.
  2. ↑ "SUGEN COMPLETES IPO, NETS $18M + | Bioworld" . BioWorld. 5 October 1994. Retrieved 2020-11-16.
  3. ↑ "Sugen Files IND For SU101/BCNU Trial - Pharmaceutical industry news". The Pharma Letter. 23 July 1997. Retrieved 2020-11-16.
  4. 1 2 Schlessinger, Joseph. "SU11248: Genesis of a New Cancer Drug". The Scientist. 19: 17–24. Archived from the original on 19 April 2005.
  5. ↑ "Making a Rush For Sugen". Bloomberg. Archived from the original on 4 November 1999.
  6. ↑ "Sugen Signs $70 Million Deal With Taiho". The Pharma Letter. 8 May 1998.
  7. ↑ "SUGEN JOINS FORCES WITH SELECTIDE + | Bioworld". BioWorld. 19 January 1993. Retrieved 2020-11-16.
  8. ↑ "Pharmacia acquires Sugen - Jun. 15, 1999". CNN Money. 15 June 1999. Retrieved 2020-11-16.
  9. ↑ "Pharmacia & Upjohn agrees to merge with Monsanto, creating $50 billion". The Pharma Letter. 20 December 1999. Retrieved 2020-11-16.
  10. ↑ Teitelman, Robert (18 February 2019). "Big Pharma Can't Resist Big Mergers. Here's Why". Barrons. Retrieved 2020-11-16.
  11. ↑ "It's official: Pfizer buys Pharmacia - Apr. 16, 2003". CNN Money. 16 April 2003. Retrieved 2020-11-16.
  12. ↑ Pettypiece, Shannon (7 June 2010). "Pfizer Drug Targets Gene Flaw to Shrink Lung Tumors (Update1)". Bloomberg Businessweek. Archived from the original on 8 June 2010.
  13. ↑ Jarvis, Lisa M. "CRIZOTINIB CHRONICLES". Chemical & Engineering News. 88: 20–21. doi:10.1021/cen-v088n030.p020.
  14. ↑ "The Spirit Of A Startup Lives On". BusinessWeek.
  15. ↑ "Pfizer 2010 annual financial review, p 25" (PDF).
  16. ↑ Berkrot, Bill (2010-06-16). "Pfizer sues Mylan over Sutent patent infringement". Reuters. Retrieved 2020-11-16.
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