The Discovery and Characterization of CFT7455:
A Potent and Selective Degrader of IKZF1/3 for the Treatment of Relapsed/Refractory Multiple Myeloma
James A. Henderson, Scott J. Eron, Andrew Good, R Jason Kirby, Samantha Perino, Roman V. Agafonov, Prasoon Chaturvedi, Bradley Class, David Cocozziello, Ashley A. Hart, Christina S. Henderson, Marta Isasa, Brendon Ladd, Matt Schnaderbeck, Michelle Mahler, Adam S. Crystal, Roy M. Pollock, Christopher G. Nasveschuk, Andrew J. Phillips, Stewart L. Fisher, David A. Proia
C4 Therapeutics, Inc
Watertown, MA USA
Disclosure Information
James A. Henderson, PhD
▪ I have the following financial relationships to disclose:
• Stockholder in: C4 Therapeutics
• Employee of: C4 Therapeutics
▪ I will not discuss off label use and/or investigational use in my presentation.
CFT7455: Potent Small Molecule IKZF1/3 Degrader with Enhanced Catalytic & Pharmacologic Properties
• IKZF1/3 are transcription factors required for cancer cell growth and survival in multiple myeloma (MM)
• IKZF1/3 degrading IMiDs are widely used in MM treatment (lenalidomide, pomalidomide)
• Relapsed/refractory MM remains a high unmet medical need
Ub
Ub
Goal: Develop an IKZF1/3 Monofunctional Degradation Activating Compound (MonoDAC) with these properties:
• Class-leading catalytic activity to enable potent, rapid, and deep target degradation
• High binding affinity to overcome IMiD resistanceIKZF1, IKZF3 degradation
• Selective to reduce off-target liabilities
• Pharmacologic profile that enables sustained
Death of myeloma cells
IKZF1/3 degradation
CFT7455
E3 Ubiquitin Ligase Complex
CRBN, cereblon; CUL4, cullin 4; DDB1, DNA damage-binding protein 1; IKZF1/3, Ikaros family zinc finger proteins 1 and 3; IMiD, immunomodulatory imide drug; monoDAC, monofunctional degradation activating compound; MM, multiple myeloma; RBX1, ring box protein 1; Ub, ubiquitin.
IKZF1/3 Degrader Lead Derived from MonoDAC Library Hit
IKZF1/3, Ikaros family zinc finger proteins 1 and 3; HiBiT; high affinity bioluminescent tag; monoDAC, monofunctional degradation activating compound; PK, pharmacokinetics; SBDD, structure-based drug design.
Need for Speed: Structural Biology Highlights Areas for Chemistry Exploration
Compound 3
monoDAC
• The monoDAC degrader binds to
CRBN and modulates the surface to accommodate an interaction with neosubstrate
• The second zinc finger of IKZF1 lands on top of the CRBN-monoDAC degrader complex
• The b-hairpin glycine interaction with the monoDAC is critical for IKZF1/3 degradation
CRBN
CRBN, cereblon; IKZF1/3, Ikaros family zinc finger proteins 1 and 3; monoDAC, monofunctional degradation activating compound; PDB: 6h0f, pomalidomide CRBN complex bound to IKZF1(ZF2). Sievers et al. Science. 2018:(2);362(6414):eaat0572. doi:10.1126/science.aat0572
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C4 Therapeutics Inc. published this content on 11 April 2022 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 11 April 2022 15:30:08 UTC.