AACR Presentation: The Discovery and Characterization of CFT7455

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