IDP

Reinforced Dynamics-Guided Discovery of Small Molecules Targeting Undruggable c-Myc

AI-driven conformational search of intrinsically disordered protein

Myc is a well-validated oncogenic target across numerous cancers, presenting significant anti-tumor potential.

The intrinsically disordered structure of c-Myc has historically rendered it a challenging "undruggable" target for small molecule therapeutics.

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The RiDYMO Platform Unlocks the Ability to Target c-Myc

In classical molecular dynamics (MD), c-Myc often becomes trapped near its initial state, limiting conformational exploration.
Reinforced Dynamics (RiD), an AI-driven enhanced sampling method, enables rapid transitions between different metastable states of c-Myc, overcoming traditional MD limitations and expanding druggable conformations.

Design Workflow

Using the RiDYMO platform, we efficiently identified DP390, a novel small molecule inhibitor that directly targets c-Myc:

SPR and STD-NMR analyses confirmed that DP390 binds directly to c-Myc, disrupting its interaction with Max. This disruption leads to c-Myc protein instability, degradation, and subsequent impairment of downstream transcriptional functions.
Cell viability assays demonstrated that DP390 significantly inhibited the proliferation of HL-60 tumor cells and induced G0/G1 phase cell cycle arrest.