FOXO4-DRI: 10MG

FOXO4-DRI (also known as Proxofim) is a synthetic D-amino acid retro-inverso peptide designed to disrupt the interaction between Forkhead Box Protein O4 (FOXO4) and the tumour suppressor p53. It was first described in a landmark 2017 Nature paper by Baar et al. from the group of Peter de Keizer at the University Medical Center Utrecht, where it was characterised as a senolytic compound - a class of agents capable of selectively clearing senescent cells from tissue. The retro-inverso design, in which the amino acid sequence is reversed and all residues use D-enantiomers rather than the natural L-form, confers substantially greater resistance to proteolytic degradation compared to conventional peptides, extending its functional half-life in biological systems.

Senescent cells - cells that have permanently exited the cell cycle but resist apoptosis - accumulate with age and are understood to drive many hallmarks of aging through the secretion of pro-inflammatory mediators (the senescence-associated secretory phenotype, or SASP). FOXO4, a transcription factor elevated in senescent cells, maintains their survival by anchoring p53 in the nucleus and preventing it from initiating apoptosis. FOXO4-DRI competitively occupies the p53-binding domain of FOXO4, freeing p53 to translocate to the mitochondria and initiate cell-intrinsic apoptosis selectively in senescent cells, leaving healthy cells unaffected.

Design Rationale: The D-retro-inverso architecture makes FOXO4-DRI protease-resistant while retaining the same three-dimensional binding surface as the natural L-sequence. This allows the peptide to penetrate cells and disrupt protein-protein interactions that would otherwise be inaccessible to standard peptide drugs.

Research Context: Studied predominantly in animal models for its ability to selectively clear senescent cells across multiple tissue types including liver, kidney, adipose, skeletal muscle, and testes. As of April 2026, no completed human clinical trials have been published. Research interest spans oncology, gerontology, and tissue engineering.

Peptide Sequence: H-D-Leu-D-Thr-D-Leu-D-Arg-D-Lys-D-Glu-D-Pro-D-Ala-D-Ser-D-Glu-D-Ile-D-Ala-D-Gln-D-Ser-D-Ile-D-Leu-D-Glu-D-Ala-D-Tyr-D-Ser-D-Gln-D-Asn-D-Gly-D-Trp-D-Ala-D-Asn-D-Arg-D-Arg-D-Ser-D-Gly-D-Gly-D-Lys-D-Arg-D-Pro-D-Pro-D-Pro-D-Arg-D-Arg-D-Arg-D-Gln-D-Arg-D-Arg-D-Lys-D-Lys-D-Arg-D-Gly-OH

Molecular Formula: C₂₀₂H₃₃₄N₈₀O₅₈

Molecular Weight: 4744.31 g/mol

CAS Number: 1639124-37-8

Form: Lyophilised Solid