Opportunities and Challenges in Developing Stearoyl-Coenzyme A Desaturase-1 Inhibitors as Novel Therapeutics for Human Disease

Abstract

This review provides an overview of stearoyl-coenzyme A desaturase-1 (SCD1) as a novel therapeutic target for metabolic disorders and other indications. Target validation is reviewed, and limitations due to incomplete knowledge of the relevant biological systems are described. Assay development, particularly for high throughput screening, and characterization of SCD1 inhibition are summarized. The progress and evolution in medicinal chemistry are discussed, specifically focusing on key attributes of the most advanced SCD1 inhibitors described in the primary literature and in patent applications. This work culminated in numerous companies identifying potent selective inhibitors, some of which progressed to early clinical development. The status of current SCD1 drug discovery programs is reviewed. Challenges are discussed, and potential new directions are indicated.

Unsaturated Fatty Acids Maintain Cancer Cell Stemness

“…Chemotherapy is effective for non-stem cells, so SCD-1 inhibition seems to be a promising therapeutic option to specifically target stem cells and prolong patient survival. Several inhibitors of SCD-1 have been developed, mostly for diabetes treatment; however, testing has not gone beyond phase II clinical trials (Zhang et al, 2014). While the trials have not been formally published, deletion of the SCD -1 gene in a mouse model reportedly causes mechanism-based adverse effects such as narrow eye fissures, alopecia, and loss of sebaceous gland function and skin abnormalities (Miyazaki et al, 2001) raising concerns that generalized blocking of SCD-1 may not be a clinically viable approach.…”

Biotechnological potential of insect fatty acid-modifying enzymes

“…Another major research goal is to uncover the mechanistic details of FA desaturation, which might enable rational design of specific inhibitors targeting either the mFADs involved in human metabolic diseases, such as diabetes or obesity [47], or the mFADs essential for pathogenic microorganisms, such as pathogenic yeasts [48][49][50] and trypanosomatids [51,52]. Basic research also aims to uncover the molecular basis of insect pheromone evolution by studying the pheromonebiosynthetic mFADs [18].…”

Structural basis for catalysis at the membrane-water interface

“…Though the active site lies outside of the membrane environment, the acyl chain of lipid II does not seem to be interacting with the protein and is not drawn out of the membrane as has been hypothesized for GtrB [72] or SCD1 [9, 84]. Here, only the sugar-peptide head groups of the lipids seem to be interacting with the active site, presenting yet another distinct mode of interaction between a lipid-modifying enzyme and a membrane embedded substrate.…”

“…The reaction is activated by a di-iron center in the presence of oxygen [83]. Disruption of normal SCD1 function has been associated with cancer, diabetes and other metabolic syndromes and is a popular target for inhibitor development in search of novel treatment of such disorders [84]. …”