A Selective Small‐Molecule c‐Myc Degrader Potently Regresses Lethal c‐Myc Overexpressing Tumors

Abstract

MYC oncogene is involved in the majority of human cancers and is often associated with poor outcomes, rendering it an extraordinarily desirable target, but therapeutic targeting of c‐Myc protein has been a challenge for >30 years. Here, WBC100, a novel oral active molecule glue that selectively degrades c‐Myc protein over other proteins and potently kills c‐Myc overexpressing cancer cells is reported. WBC100 targets the nuclear localization signal 1 (NLS1)–Basic–nuclear localization signal 2 (NLS2) region of c‐Myc and induces c‐Myc protein degradation through ubiquitin E3 ligase CHIP mediated 26S proteasome pathway, leading to apoptosis of cancer cells. In vivo, WBC100 potently regresses multiple lethal c‐Myc overexpressing tumors such as acute myeloid leukemia, pancreatic, and gastric cancers with good tolerability in multiple xenograft mouse models. Identification of the NLS1–Basic–NLS2 region as a druggable pocket for targeting the “undruggable” c‐Myc protein and that single‐agent WBC100 potently regresses c‐Myc overexpressing tumors through selective c‐Myc proteolysis opens new perspectives for pharmacologically intervening c‐Myc in human cancers.

Co‐Targeting c‐Myc and Bcl‐2 by Oral Small Molecule Combination of WBC100 and Venetoclax Effectively Controls Acute Myeloid Leukemia in Preclinical Models

“…We selected the MOLM‐13 cell line since it is resistant to AML standard‐of‐care chemotherapeutic agent idarubicin (IDA) as we previously reported. [ 15 ] After confirmation of AML engraftment, the mice were randomly assigned to four groups and orally administered with the vehicle, low doses of WBC100 (0.4 mg kg −1 ) or VEN (50 mg kg −1 ), or both. After 2 weeks of treatment, quantitation of MOLM‐13‐Luc luminescence via in vivo imaging showed that the leukemic burden in the WBC100/VEN combination group nearly vanished ( p <0.0001) while the single agent VEN group ( p = 0.0523, non‐significant) only showed slightly lower photon intensity (leukemia burden) than the vehicle group and soon succumbed to death ( Figure A).…”

“…Our recent studies have shown that WBC100 is a novel orally active smallmolecule c-Myc inhibitor that potently regresses c-Myc-high tumors via the degradation of c-Myc protein. [15] Venetoclax (VEN) is an oral Bcl-2 inhibitor, but single-agent VEN results in only ≈20% overall response rate. [16] Therefore, we used a panel of various AML cell lines to evaluate synergistic activity between two oral small molecules WBC100 and VEN.…”

Structure Influence of Amine‐Containing Additives on the Solution State and Out‐of‐Plane Conductivity of PEDOT:PSS for Efficient Organic Solar Cells

“…Molecular simulations were performed on these additives with the calculated electrostatic potential (ESP) distributions displayed in Figure 1b for investigating the additive interactions with the semiconductors, which are often due to dipole interactions. [44] Evidentially, the amine-containing organic molecules all display high electrostatic negativity position due to the lone pair electrons on the nitrogen atom. It is interesting to observe that the lone pair electrons from OPD and PPD situate on both sides of the molecule plane while MPD and aniline display the lone pair electrons in-plane of the molecule due to the interaction with the neighboring hydrogen atoms.…”

Rational drug design targeting intrinsically disordered proteins

“…Omomyc competes with c‐Myc to form a heterodimer with MAX or form a homodimer itself that binds c‐Myc targeted DNA 219 . The other is WBC100 (http://clinicaltrials.gov Identifier: NCT05100251), a small‐molecule ligand that can degrade c‐Myc 220 . WBC bound to the folded NLS1‐Basic‐NLS2 region of c‐Myc and pulled down the ubiquitin E3 ligase CHIP.…”

“…219 The other is WBC100 (ClinicalTrials.gov Identifier: NCT05100251), a small-molecule ligand that can degrade c-Myc. 220 WBC bound to the folded NLS1-Basic-NLS2 region of c-Myc and pulled down the ubiquitin E3 ligase CHIP. Combined with the evidence that WBC100 caused c-Myc degradation through CHIP-mediated 26S proteasome pathway, it was believed to be a molecular glue.…”