Sulfatase inhibitors: a patent review

Abstract

Introduction: Steroid sulfatase (STS) converts sulfated hormones to free hormones of importance in hormone-dependent diseases such as breast cancer and endometriosis. Carbohydrate sulfatases degrade complex carbohydrates as part of normal cellular turnover; certain lysosomal storage disorders (LSDs) involve defective processing of sulfated glycosaminoglycans by mutant sulfatases.

Areas covered: Aryl sulfamates have been developed as STS inhibitors, and STX64 and PGL2001 are under evaluation in Phase I and II clinical trials for treatment of endometrial and metastatic breast and prostate cancers and endometriosis. Dual-acting compounds have emerged that are aromatase inhibitors (AIs), selective estrogen receptor antagonists, or inhibitors of microtubule polymerization. Sulfamidase inhibitors as pharmacological chaperones to assist maturation of folding-defective mutants for the treatment of Sanfilippo type A disease are under investigation. Coverage: The patent literature after the mid-1990s.

Expert opinion: The failure of STX64 in a Phase II monotherapy clinical trial should not dissuade further investigations in multidrug regimens, particularly in combination with AIs. The recent development of dual-acting compounds may enhance the potential for success in the clinic. Further investigations into aryl sulfamates are required to clarify the molecular mechanism of action; additionally, new reversible sulfatase inhibition concepts are needed for the development of pharmacological chaperones for sulfatase LSDs.

Keywords::

• aromatase inhibitors
• EMATE
• endometriosis
• estrogen-dependent breast cancer
• irosustat
• lysosomal storage disorders
• PGL2001
• Sanfilippo type A
• steroid sulfatase
• STX64

Notes

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