Accelerated bottom-up drug design platform enables the discovery of novel stearoyl-CoA desaturase 1 inhibitors for cancer therapy

Abstract

Here we present an innovative computational-based drug discovery strategy, coupled with machine-based learning and functional assessment, for the rational design of novel small molecule inhibitors of the lipogenic enzyme stearoyl-CoA desaturase 1 (SCD1). Our methods resulted in the discovery of several unique molecules, of which our lead compound SSI-4 demonstrates potent anti-tumor activity, with an excellent pharmacokinetic and toxicology profile. We improve upon key characteristics, including chemoinformatics and absorption/distribution/metabolism/excretion (ADME) toxicity, while driving the IC50 to 0.6 nM in some instances. This approach to drug design can be executed in smaller research settings, applied to a wealth of other targets, and paves a path forward for bringing small-batch based drug programs into the Clinic.

Aberrant lipid metabolism as a therapeutic target in liver cancer

“…In vitro administration of these novel inhibitors to breast, colon, liver, ovarian, endometrial, thyroid, prostate, and lung cancer, as well as melanoma cell lines resulted in attenuated cell proliferation while having no effect upon normal primary cells in culture (i.e. renal, ovarian, and breast) [63]. Additionally, the lead compound for development, SSI-4 demonstrated excellent bioavailability and tumor suppression in patientderived xenograft models of clear cell renal cell carcinoma [63].…”

“…In more recent years, SCD1 inhibitors were discovered to also be anticancer agents and shown to inhibit tumor growth in numerous murine in vivo studies that include prostate, breast, liver, renal, and lung cancers [17,52,53,[63][64][65]. An example of recently discovered SCD1 inhibitors, von Roemeling et al developed and tested a novel computational-based drug discovery method aimed at development of a novel SCD1 inhibitor.…”

“…renal, ovarian, and breast) [63]. Additionally, the lead compound for development, SSI-4 demonstrated excellent bioavailability and tumor suppression in patientderived xenograft models of clear cell renal cell carcinoma [63]. Ma et al also demonstrated that pharmacologic SCD1 inhibition with this novel compound, SSI-4, in a previously developed sorafenib resistant HCC cell line, effectively mitigated sorafenib resistance by induction of ER stress and apoptotic cell death [54].…”

Protein informatics combined with multiple data sources enriches the clinical characterization of novel TRPV4 variant causing an intermediate skeletal dysplasia

“…The p.K801E tetramer still forms a complex but is not as tightly held together and the pore becomes more disordered and has less regular structure than the wild‐type protein (Figure c), which accounts for lowering its interaction potential with partner proteins and the loss of attractive G (Caulfield, ; Caulfield & Devkota, ; Caulfield & Medina‐Franco, ; López‐Vallejo et al., ; Reumers et al., ; Schymkowitz et al., ; Zhang et al., ). Further use of protein‐level knowledge as a diagnostic tool for clinician continues to provide new insights and help aid in the development of a database (Caulfield et al., ; Harris et al., ; Richter et al., ; von Roemeling et al., ).…”

Stearoyl-CoA desaturase mediated monounsaturated fatty acid availability supports humoral immunity

“…1F). This dramatic accumulation of MUFAs was dependent on SCD activity, because treatment with an SCD specific inhibitor, SSI-4 21 , largely reversed it ( Fig. 1F).…”