ARN22089 / University of California - LARVOL DELTA

Discovery of CDC42 Inhibitors with a Favorable Pharmacokinetic Profile and Anticancer In Vivo Efficacy. (PubMed, J Med Chem) - "We previously reported trisubstituted pyrimidine lead compounds, namely, ARN22089 and ARN25062, which block the interaction between CDC42 with its specific downstream effector, a PAK protein...Out of the 25 compounds here reported, compound 15 (ARN25499) stands out as the best lead compound with an improved pharmacokinetic profile, increased bioavailability, and efficacy in an in vivo PDX tumor mouse model. Our results indicate that these CDC42 inhibitors represent a promising chemical class toward the discovery of anticancer drugs, with ARN25499 as an additional lead candidate for preclinical development."

Journal • PK/PD data • Preclinical • Oncology

Design, Synthesis, In Vitro and In Vivo Characterization of CDC42 GTPase Interaction Inhibitors for the Treatment of Cancer. (PubMed, J Med Chem) - "Recently, we reported the discovery of a novel lead compound, ARN22089, which blocks the interaction of CDC42 GTPases with specific downstream effectors...We discovered and optimized two novel inhibitors (27, ARN25062, and 28, ARN24928), which are optimal back-up/follow-up leads with favorable drug-like properties and in vivo efficacy in PDX tumors. These findings further demonstrate the potential of this class of CDC42/RHOJ inhibitors for cancer treatment, with lead candidates ready for advanced preclinical studies."

Journal • Preclinical • Melanoma • Oncology • Solid Tumor • BRAF • CDC42 • RHOJ

Structure-based design of CDC42 effector interaction inhibitors for the treatment of cancer. (PubMed, Cell Rep) - "ARN22089 selectively blocks CDC42 effector interactions without affecting the binding between closely related GTPases and their downstream effectors. Taken together, we identify a class of therapeutic agents that influence tumor growth by modulating CDC42 signaling in both the tumor cell and its microenvironment."

Journal • Melanoma • Oncology • Solid Tumor • BRAF

[VIRTUAL] Structure-based design of CDC42/RHOJ effector inhibitors for the treatment of cancer (AACR-II 2020) - "Short term treatment of nascent melanoma tumors with ARN22089 halted the growth of BRAF mutant autochthonous mouse melanoma tumors, slowed the growth of melanoma patient-derived xenografts, and induced tumor necrosis in PDX models. In summary, we describe a multidisciplinary structure-based drug discovery platform that can identify new RHO family allosteric inhibitors and use this system to identify RHOJ inhibitors that block tumor growth in vivo."

Melanoma • Oncology • Solid Tumor • BRAF • RAC1