ASH Poster 2023
A Dual-specific Inhibitor Of Rock/Aurk, Rr-1752, For Primary Myelofibrosis
Authors: L. Zhang, K. McGinnis, P. Gonzales, M. Murray, E. Cluff, MD B. Mia, C. Schaniel, J. Mascarenhas, A. M. Miller, R. Hoffman, and S. Gately Translational Drug Development, Scottsdale, AZ
Introduction: Myelofibrosis (MF) is a clonal myeloproliferative neoplasm (MPN) characterized by driver mutations in JAK2, CALR, and MPL resulting in constitutive activation of JAK-STAT signalling1. Abnormalities in megakaryocyte (MK) numbers and morphology are common features of MF. The MK endomitosis and demarcation membrane system (DMS) are regulated by signaling pathways including Aurora kinase (AURK) and RhoA/ROCK/MLCII2,3. AURK and ROCK are overexpressed in MPN and are linked to dysregulated MKs of patients with MPN.
We developed and tested the safety activity of RR1752, a dual-specific inhibitor of ROCK and AURK, in a series of studies to characterize the potential of this drug for MF treatment.
Conclusions:
- RR-1752 inhibited colony formation in HEL-92.1.7 and UKE-1 in MethoCult™️, IC50 = 25.2 nM and 54.6 nM, respectively.
- RR-1752 significantly decreased pSTAT3 in stimulated human PBMC and phosphorylated myosin light chain (pMLC) in HEL-92.1.7 and UKE-1 confirming on-target action.
- RR-1752 induced cell cycle arrest in HEL-92.1.7 and UKE-1 specifically at the G2/M checkpoint consistent with role of ROCK in cell cycle progression5.
- No significant toxicity of RR-1752 was observed in healthy mice or rats during the study period: QD 100 mg/kg or BIW 200 mg/kg for 3 weeks in mice; QD 100 mg/kg for 2 weeks in rats.
- RR-1752, 25 mg/kg PO daily resulted in a significant (p<0.01) improvement in median survival (31 days) compared to ruxolitinib alone, 45 mg/kg PO daily (21 days) in the human MPN cell HEL92.1.7 xenograft mouse model.
- RR1752 is a novel dual-specific inhibitor of ROCK/AURK that warrants further investigation for patients with myeloproliferative neoplasms.
