Together with our collaborator, Dr. Konstantin Petrukhin at Columbia University (https://www.vagelos.columbia.edu/profile/konstantin-petrukhin-phd), we identified selective RBP4 antagonists, such as clinically investigated tinlarebant, that dissociate circulating RBP4−TTR−retinol complexes, reduce serum RBP4 levels, and inhibit bisretinoid synthesis in models of enhanced retinal lipofuscinogenesis. However, the release of TTR by selective RBP4 antagonists may be associated with TTR tetramer destabilization and, potentially, TTR amyloid formation. 

We have been engaged in an NIH-funded drug discovery project in collaboration with Columbia University that focused on the identification of bispecific RBP4 antagonist−TTR tetramer kinetic stabilizers, which may be especially important as a therapy for atrophic AMD patients who have another common age-related comorbidity, senile systemic amyloidosis (SSA), a nongenetic disease associated with wild-type TTR misfolding. These bispecific compounds also present potential therapeutic utility for treating Stargardt disease, an inherited form of macular degeneration. We have identified lead compound (±)-ACPHS-52 that exhibits a desirable ADME profile, PK characteristics, and exhibits potent RBP4 lowering capability in vivo. (±)-ACPHS-52 was exhibits potent TTR tetramer stabilization activity. We are currently developing (R)-ACPHS-62 via NIH support (NIH 1R61EY036287), and expect to initiate IND-enabling studies in 2026.

Funding: NIH 5R01EY028549, NIH 2R01EY028549-04A1, NIH 1R61EY036287

Cioffi, C. L.; Muthuraman, P.; Raja, A.; Varadi, A.; Racz, B.; Petrukhin, K.  Discovery of bispecific antagonists of retinol binding protein 4 that stabilize transthyretin tetramers: scaffolding hopping, optimization, and preclinical pharmacological evaluation as a potential therapy for two common age-related comorbidities. J. Med. Chem. 2020, 63, 11054-11084; PMCID:PMC9578044 PMID: 32878437.

Petrukhin, Konstantin; Racz, Boglarka; Varadi, Andras; Muthuraman, Parthasarathy; Raja, Arun; Cioffi, Christopher L., WO2022020305 A2 2022-01-27.