Biology subjects

Bum-Erdene, K.

Publications and source records attributed to Bum-Erdene, K..

4 recordsLinked to original sources

bioRxiv2026

Fragment Covalent Bond Formation at SOS1 Tyr-884 Inhibits KRAS Nucleotide Exchange

The activation of the KRAS oncogene from its inactive GDP-bound state to its active GTP-bound state is mediated by Son of Sevenless (SOS) exchange factors. Small-molecule inhibition of SOS1 has been achieved, with three compounds currently in clinical trials. These compounds bind to SOS1 and disrupt a crucial interaction between SOS1 Tyr-884 and KRAS Arg-73. Here, we screen libraries of aryl sulfonyl fluorides to explore covalent bond formation at Tyr-884 as a strategy for covalent inhibition of SOS1-KRAS binding. Initially, ten fragments were tested and several inhibited KRAS nucleotide exchange by SOS1. X-ray crystal structures revealed that one reaction site for the fragments was Tyr-884, but mass spectrometry and nucleotide exchange assays with wild-type and mutant SOS1 indicated additional reaction sites. To identify candidates specific to Tyr-884, we conducted a larger screen and identified fragment 11 (SOF-599). The fragment formed an adduct predominantly at Tyr-884 and inhibited KRAS nucleotide exchange by SOS1 in a time- and concentration-dependent manner. Fragment 11 (SOF-599) exhibited a half-maximal inactivation concentration (KI) of 12 micromolar and a reaction half-life of 6 h. These findings establish 11 (SOF-599) as a promising starting point for the development of covalent SOS1 inhibitors as an alternative strategy to existing non-covalent antagonists.

pharmacology and toxicology↗

bioRxiv2026

A Fragment Screen Identifies Acrylamide Covalent Inhibitors of the TEAD/YAP Protein-Protein Interaction

TEA domain (TEAD) proteins bind co-activator Yes-associated protein (YAP) to regulate the expression of target genes of the Hippo pathway. The TEAD*YAP protein-protein interaction is not druggable, but TEADs possess a unique and deep palmitate pocket with a highly conserved cysteine located outside the TEAD*YAP protein-protein interaction interface. Here, we screen a fragment library of acrylamide electrophiles and identify a fragment that forms an adduct with the conserved palmitate pocket cysteine and inhibits TEAD4 binding to YAP. Synthesis of a focused set of derivatives and time- and concentration-dependent studies with four TEADs provide reaction rates and binding constants. Co-crystal structures of fragments bound to TEAD2 and TEAD3 reveal reaction at the conserved palmitate pocket cysteine but also at another less conserved cysteine located in the palmitate pocket of TEAD2 closer to the TEAD*YAP interface. These fragments provide a starting point for the development of allosteric acrylamide small-molecule covalent TEAD*YAP inhibitors.

biochemistry↗

bioRxiv2026

Degradation of the TEAD-YAP/TAZ Transcription Factor Complex by Heterobifunctional Small Molecules that Bind to the TEAD Allosteric Lipid Pocket

Central kinases of the Hippo tumor suppressor pathway phosphorylate the transcriptional coactivators YAP and TAZ to sequester them in the cytoplasm. In cancer, Hippo pathway kinases have reduced activity, leading to translocation of YAP and TAZ into the nucleus where they engage TEADs and other transcription factors. Here, we explore whether heterobifunctional small molecules that bind to the TEAD allosteric lipid-binding pocket can degrade the TEAD*YAP/TAZ complex. We design and synthesize heterobifunctional molecules that consist of flufenamic acid analogs that bind to the allosteric TEAD lipid pocket, a long and flexible linker, and thalidomide to engage E3 ubiquitin ligase component cereblon. The bifunctional compounds promote ternary complex formation in biochemical assays and mammalian cells but exhibited modest degradation of TEAD, YAP, and TAZ in cancer cells. Methyl ester analogs of these compounds led to substantial proteasomal degradation of the TEAD*YAP/TAZ complex in cancer cells. This work provides a strategy for depletion of nuclear YAP and TAZ and for exploration of their TEAD-dependent and TEAD-independent activities in vivo.

pharmacology and toxicology↗

bioRxiv2021

Overcoming microenvironment-mediated chemoprotection through stromal Galectin-3 inhibition in acute lymphoblastic leukemia

Environmentally-mediated drug resistance in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) significantly contributes to relapse. Stromal cells in the bone marrow environment protect leukemia cells by secretion of chemokines as cues for BCP-ALL migration towards, and adhesion to, stroma. Stromal cells and BCP-ALL cells communicate through stromal galectin-3. Here, we investigated the significance of stromal galectin-3 to BCP-ALL cells. We used CRISPR/Cas9 genome editing to ablate galectin-3 in stromal cells and found that galectin-3 is dispensable for steady-state BCP-ALL proliferation and viability. However, efficient leukemia migration and adhesion to stromal cells are significantly dependent on stromal galectin-3. Importantly, loss of stromal galectin-3 production sensitized BCP-ALL cells to conventional chemotherapy. We therefore tested novel carbohydrate-based small molecule compounds (Cpd14 and Cpd17) with high specificity for galectin-3. Consistent with results obtained using galectin-3-knockout stromal cells, treatment of stromal-BCP-ALL co-cultures inhibited BCP-ALL migration and adhesion. Moreover, these compounds induced anti-leukemic responses in BCP-ALL cells including a dose-dependent reduction of viability and proliferation, induction of apoptosis and, importantly, inhibition of drug resistance. Collectively, these findings indicate galectin-3 regulates BCP-ALL cell responses to chemotherapy through the interactions between leukemia cells and the stroma, and show that a combination of galectin-3 inhibition with conventional drugs can sensitize the leukemia cells to chemotherapy.

cancer biology↗