Abstract DDT01-04: Pharmacological profile and anti-tumor properties of LXH254, a highly selective RAF kinase inhibitor
Authors: Stuart Darrin D. , Shao Wenlin , Mishina Yuji , Feng Yun , Caponigro Giordano , Cooke Vesselina G. , Rivera Stacey , Shen Fang , Korn Joshua , Griner Lesley A. Mathews , Nishiguchi Giselle , Taft Benjamin , Wan Lifeng , Subramanian Sharadha , Lou Yan , Setti Lina , Burger Matthew , Tamez Victor , Rico Alice , Aversa Robert , Tellew John , Haling Jacob R. , Polyakov Valery , Lambert Amy , Zang Richard , Abbema Ann Van , Hekmat-Nejad Mohamad , Amiri Payman , Singh Mallika , Keen Nicholas , Dillon Michael P. , Lees Emma , Sellers William R. , Ramurthy Savithri 
Published: August 2018

Abstract
The mitogen-activated protein kinase (MAPK) signaling pathway is frequently activated in human cancers due to genetic alterations that can occur at multiple nodes, the most prevalent of which are mutations in RAS or BRAF. While BRAFV600 mutant tumors are responsive to RAF inhibitors such as dabrafenib and vemurafenib, these drugs are ineffective in RAS mutant cancers and tumors expressing other RAF mutations. CRAF kinase functions as a critical effector in mutant RAS and Class II/III BRAF mutant tumors and plays a role in feedback-mediated pathway reactivation following MEK inhibition. Thus, selective inhibitors that potently inhibit the activity of CRAF could be both effective in blocking mutant RAS and BRAF signaling and in inhibiting feedback-mediated activation in combination with a MEK inhibitor. LXH254 is a type II ATP-competitive inhibitor that inhibits both B- and CRAF kinase activities at picomolar concentrations with a high degree of selectivity against a panel of 456 human kinases and in cell-based assays. LXH254 not only inhibits MAPK signaling activity in tumor models harboring BRAFV600 mutation, but also inhibits mutant N- and KRAS-driven signaling due to its ability to inhibit both RAF monomers and dimers with similar potencies. LXH254 is orally bioavailable, demonstrates a direct PK/PD relationship and causes tumor regression in multiple cell line and primary human tumor derived xenograft models at well-tolerated doses. LXH254 represents a next generation RAF inhibitor that is differentiated from other RAF inhibitors in this class due to the high degree of selectivity. In preclinical efficacy and toxicology studies, LXH254 demonstrated a relatively wide therapeutic index which should enable effective interrogation of RAF inhibition in patients with decreased risk for off-target toxicity. LXH254 is currently in a Phase I trial in patients with solid tumors expressing MAPK pathway mutations.
Citation Format: Darrin D. Stuart, Wenlin Shao, Yuji Mishina, Yun Feng, Giordano Caponigro, Vesselina G. Cooke, Stacey Rivera, Fang Shen, Joshua Korn, Lesley A. Mathews Griner, Giselle Nishiguchi, Benjamin Taft, Lifeng Wan, Sharadha Subramanian, Yan Lou, Lina Setti, Matthew Burger, Victor Tamez, Alice Rico, Robert Aversa, John Tellew, Jacob R. Haling, Valery Polyakov, Amy Lambert, Richard Zang, Ann Van Abbema, Mohamad Hekmat-Nejad, Payman Amiri, Mallika Singh, Nicholas Keen, Michael P. Dillon, Emma Lees, William R. Sellers, Savithri Ramurthy. Pharmacological profile and anti-tumor properties of LXH254, a highly selective RAF kinase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr DDT01-04.