Associate Scientific Director Bristol-Myers Squibb Belle Mead, New Jersey
Ligand-directed degrader (LDD) drugs represent a frontier in targeted disease therapy by selectively degrading disease-causing proteins, offering heightened precision and efficacy in treatment. Despite their therapeutic promise, the inherent chirality and substantial molecular size of these compounds pose significant development challenges. This study focuses on establishing a comprehensive control strategy for BMS-123, a pioneering ligand-directed degrader molecule.
Central to the function of BMS-123 is its glutarimide ring, which binds specifically to the protein cereblon (CRBN). The glutarimide ring fits precisely into a unique pocket within CRBN, modulating its role as an E3 ubiquitin ligase. This interaction is crucial for the drug's efficacy, relying heavily on the ring's specific conformation and hydrogen bonding capabilities to ensure effective CRBN binding.
The chirality of the glutarimide ring is pivotal, as it dictates binding specificity to target proteins. The spatial arrangement of atoms creates one chiral form that fits effectively into the protein's binding pocket, enabling selective interactions. Consequently, characterizing chirality, stereoisomers, and the associated polymorphs of these complex molecules is essential.
To address these challenges, we have employed an integrative suite of advanced techniques—Powder X-ray Diffraction (PXRD), Single Crystal X-ray Diffraction (SXRD), two-dimensional (2D) solid-state Nuclear Magnetic Resonance (ssNMR), Terahertz Spectroscopy, and Crystal Structure Prediction (CSP). This multidisciplinary approach allows us to decipher the polymorphic mixtures of diastereoisomers, providing critical insights into the structural specifics of BMS-123.
This comprehensive methodology not only elucidates the API's structural dynamics but also informs a robust control strategy for BMS-123’s crystallization and manufacturing processes. By preemptively addressing potential regulatory queries, we set a strategic pathway for this compound's successful development and commercialization.
In conclusion, the synergistic application of these analytical techniques equips us with a detailed understanding of BMS-123’s structural landscape, paving the way for effective control strategies that ensure consistent quality and performance of this promising ligand-directed degrader.
Learning Objectives:
Characterizing chirality, stereoisomers, and the associated polymorphs of these complex LDD molecules is essential and complex, and requires advanced analytical characterization.
This methodology clarifies API structure and polymorphic space and supports BMS-123 crystallization control, addressing regulatory concerns to ensure strategic development and successful commercialization of the compound.
These analytical techniques provide detailed insights into BMS-123's structure, enabling effective control strategies to ensure consistent quality and performance of this promising ligand-directed degrader.
