Biology subjects

Layng, F. I. A. L.

Publications and source records attributed to Layng, F. I. A. L..

4 recordsLinked to original sources

bioRxiv2026

Reversible, Orally Bioavailable Small-Molecule Inhibitors Occupy the Substrate Tunnel of the Thioesterase Domain of Fatty Acid Synthase

Fatty acid synthase (FASN) is the sole enzyme capable of lipogenesis in cells and is upregulated in many cancers. Herein we report the discovery and development of SBP-5917 (78S), a novel, reversible, small-molecule probe which targets the thioesterase (TE) domain of FASN. SBP-5917 and other compounds in the series possess IC50 < 1 M and < 5 M for inhibiting recombinantly purified FASN-TE and cellular FASN respectively. Co-crystal structures of our inhibitors bound to the FASN-TE domain show that they are positioned in the substrate tunnel of the enzyme. Biochemical and biophysical analyses quantify the strength of compound binding and demonstrate their selectivity for FASN-TE. Preliminary pharmacokinetic studies indicate promising in vivo potency for many of the compounds in the series. SBP-5917 is the first structurally validated, reversible inhibitor of FASN-TE with demonstrated cellular target engagement and can serve as a chemical probe to investigate FASN as a therapeutic target.

cell biology↗

bioRxiv2025

ULK1/2 Inhibitors that Degrade ATG13 Effectively Target KRAS-Mutant Cancers

KRAS mutations drive tumorigenesis in multiple cancer types, including lung and pancreatic cancer. Autophagy is a cell survival pathway that supports tumor growth under metabolic stress and has been proposed to be a potential therapeutic avenue specifically in KRAS mutant cancers. The Unc-51-like ATG-activating kinases 1 and 2 (ULK) initiate the earliest regulated steps of autophagy and are the only protein kinases in the canonical autophagy pathway, thus making them attractive therapeutic targets for KRAS mutant tumors. We show here that genetic depletion of ULK1 or ATG13, core components of the ULK1 complex, in KRAS mutant lung and pancreatic cancer cell lines results in growth inhibition. Previously, we developed small molecule ULK1 inhibitors that not only inhibit ULK kinase activity but also induced the degradation of other core members of the ULK complex including ATG101 and ATG13. Therefore, we developed a high-throughput screening (HTS) assay in which ATG13 was HiBiT-tagged in KRAS mutant lung cancer cells to evaluate ULK inhibitors for ATG13 degradation. Using this approach, we discovered a lead ULK inhibitor, SBP-1750, that potently inhibited ULK activity, promoted robust ATG13 degradation, impaired ATG, and induced KRAS mutant cancer cell death. Studies in a KRAS-mutant orthotopic syngeneic pancreatic cancer model show that oral treatment with SBP-1750 significantly reduced tumor growth. Pharmacokinetic analysis of SBP-1750 indicates favorable drug exposure and pharmacodynamic analysis confirms ATG13 degradation in vivo, mirroring in vitro results. Finally, immunohistochemical staining of orthotopic pancreatic tumors reveals a significant increase in CD4 and CD8 T cell infiltration upon treatment, suggesting that SBP-1750 enhances anti-tumor immunity. These findings support further development of SBP-1750 as a novel ATG-targeting cancer therapy.

cancer biology↗

bioRxiv2025

Synthesis and Characterization of ULK1/2 Kinase Inhibitors that Inhibit Autophagy and Upregulate Expression of Major Histocompatibility Complex I for the Treatment of Non-Small Cell Lung Cancer

Autophagy inhibition represents a promising therapeutic approach for the management of various cancers including non-small cell lung cancer (NSCLC). We previously reported SBP-7455, a dual inhibitor of unc-51-like kinase 1 (ULK1) and its homologue ULK2, and described its effects on triple-negative breast cancer (TNBC) cells. Herein we report the design, synthesis, and characterization of SBP-5147 and SBP-7501, two new dual ULK1/2 inhibitors that are cytotoxic against NSCLC cells, inhibit autophagic flux in A549 cells, and present greater oral exposure than SBP-7455 at a lower dose. In addition, SBP-5147 effectively modulates autophagy and increases the expression of major histocompatibility complex (MHC) class I in NSCLC cells, which may support the rationale for ULK1/2 inhibition as a strategy to overcome resistance to immunotherapy. Together these data support the use of ULK inhibitors as part of a cancer treatment strategy, both as a single agent as well as in combination with current therapies.

cancer biology↗

bioRxiv2019

Exosome-mediated MIR211 modulates tumor microenvironment via the DUSP6-ERK5 axis and contributes to BRAFV600E inhibitor resistance in melanoma.

The microRNA MIR211 is an important regulator of melanoma tumor cell behavior. Previous studies suggested that in certain tumors, MIR211 acted as a tumor suppressor while in others it behaved as an oncogenic regulator. When MIR211 is expressed in BRAFV600E-mutant A375 melanoma cells in mouse xenografts, it promotes aggressive tumor growth accompanied by increased cellular proliferation and angiogenesis. We demonstrate that MIR211 is transferred to adjacent cells in the tumor micro-environment via exosomes. Cross-species genome-wide transcriptomic analysis showed that human tumor-derived MIR211 interacts with the mouse transcriptome in the tumor microenvironment, and activates ERK5 signaling in human tumor cells via the modulation of a feedback loop. Human miR211 directly inhibits human DUSP6 protein phosphatase at the post-transcriptional level. We provide support for the hypothesis that DUSP6 inhibition conferred resistance of the human tumor cells to the BRAF inhibitor vemurafenib and to the MEK inhibitor cobimetinib, with associated increases in ERK5 phosphorylation. These findings are consistent with a model in which MIR211 regulates melanoma tumor proliferation and BRAF inhibitor resistance by inducing ERK5 signaling within the complex tumor microenvironment. We propose that the MIR211-ERK5 axis represents an important and sensitive regulatory arm in melanoma with potential theranostic applications.

cancer biology↗