Abstract 2172: ON 123300, an orally administered novel CDK4/6 + ARK5 inhibitor, exhibits potent antitumor activity in vivo: comparative studies with Palbociclib
Authors: Patel Shraddha , Pancholi Priya , Visal Tanvi , Samant Amruta , Kansara Dhvanir , Rajadhyaksha V J. , Hoffman Benjamin S. , Maniar Manoj , Sehdev Vikas 
Published: July 2017

Abstract
Background: The overexpression of cyclin-dependent kinases 4/6 (CDK4/6) is known to cause cell cycle dysregulation in certain cancer types, making these cell cycle kinases attractive targets for pharmacological inhibition. The effectiveness of first-generation non-selective cyclin-dependent kinases, such as roscovitine and flavopiridol, was hampered by toxicities, leading to the development of second-generation compounds like IBRANCE®/Palbociclib that specifically inhibit CDK4 and 6. ON 123300 is a third-generation potent CDK4/6 inhibitor that also inhibits ARK5 with low nanomolar potency and has the potential to improve upon second-generation compounds. Previous studies have demonstrated the inhibitory effect of single-agent ON 123300 in various pre-clinical cancer models of MM and leukemia. In this study, we investigated the comparative therapeutic potential of ON 123300 as an oral anticancer agent and a second-generation inhibitor, Palbociclib, in xenografted Rb+ve mouse models.
Methods: MDA-MB-435S xenografted mice were treated once a day for 21 days with ON 123300 (125mg/kg) or Palbociclib (125mg/kg). Tumor volumes were measured and peripheral blood was gathered to evaluate the effects on hematological parameters. Separately, Western blot analyses were performed to determine the effect of CDK4/6 inhibition on p-Rb following intra-tumoral treatment with ON 123300 (2.5µM) or Palbociclib (2.5µM).
Results: ON 123300 and Palbociclib reduced tumor growth with an equivalent magnitude during the 21-day treatment period, suggesting that the two compounds were equally effective in this model. Both compounds decreased RBC and platelet counts, however Palbociclib had a
more prominent and statistically significant (P≤0.05) inhibitory effect on neutrophil counts when compared to ON 123300 (30.70 ± 3.55 vs. 45.10 ± 2.04). Western blot analysis of tumor tissues demonstrated equivalent effects on p-Rb for both compounds.
Conclusions: Xenograft data indicates that a third-generation CDK4/6 inhibitor, ON 123300, is as effective as Palbociclib in an Rb+ve xenograft model. Moreover, this study also suggests that ON 123300 may have the added advantage of reduced neutropenia compared to Palbociclib. Prior preclinical data suggest that ON 123300 may be efficacious in Rb-ve tumors, where second-generation compounds have diminished single-agent
activity, and our ongoing studies are aimed at further characterizing the in vivo activity of ON 123300 in this setting.
Citation Format: Shraddha Patel, Priya Pancholi, Tanvi Visal, Amruta Samant, Dhvanir Kansara, V J. Rajadhyaksha, Benjamin S. Hoffman, Manoj Maniar, Vikas Sehdev. ON 123300, an orally administered novel CDK4/6 + ARK5 inhibitor, exhibits potent antitumor activity in vivo: comparative studies with Palbociclib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2172. doi:10.1158/1538-7445.AM2017-2172