Abstract 791: BLU-285, the first selective inhibitor of PDGFRα D842V and KIT Exon 17 mutants
Authors: Evans Erica K. , Hodous Brian L. , Gardino Alexandra K. , Davis Alison , Zhu Julia , Shutes Adam , Kim Joseph L. , Wilson Kevin J. , Wilson Doug , Zhang Yulian , Chu Tat , Kohl Nancy E. , Kadambi Vivek , Guzi Timothy , Lengauer Christoph 
Published: August 2015

Abstract
The advent of imatinib therapy in gastrointestinal stromal tumor (GIST) has been transformative, altering the treatment of advanced disease in the majority of patients from supportive care and poor prognosis to a median 24-month progression free survival in the first line setting. However, for 20% of patients with gastric GIST, imatinib shows no therapeutic benefit. These patients are characterized by the amino acid substitution D842V in the PDGFRα protein; this mutation results in ligand-independent activation of PDGFRα and is insensitive to all small molecule inhibitors approved for GIST. When metastatic, the prognosis for PDGFRα D842V GIST is dire, with median overall survival of 12 months. Starting with a novel chemical library optimized for kinase selectivity and potency, we have identified BLU-285, a small molecule kinase inhibitor that potently inhibits PDGFRα D842V mutant activity in vitro (IC50 = 0.5 nM) and PDGFRα D842V autophosphorylation in the cellular setting (IC50 = 30 nM). We have observed that in addition to PDGFRα D842V, BLU-285 is also a potent inhibitor of the analogous KIT mutation, D816V in KIT Exon 17 (IC50 = 0.5nM). KIT D816 mutations have been identified in several human diseases such as systemic mastocytosis (SM), acute myeloid leukemia (AML), and as resistance mutations in second and third line GIST, after imatinib and sunitinib failure. Cellular assays measuring inhibition of KIT mutant autophosphorylation confirm the activity of BLU-285 against the KIT D816 mutants D816V (HMC1.2 cells, IC50 = 3 nM) and D816Y (P815 cells, IC50 = 22 nM) as well as other KIT Exon 17 mutants such as N822K (Kasumi cells, IC50 = 40 nM) found in treatment-refractory GIST. In vivo, BLU-285 is a well-tolerated, orally bioavailable agent that achieves dose dependent tumor growth inhibition in a D816Y-driven xenograft model. A PK-PD-efficacy relationship with BLU-285 has been established demonstrating that tumor regression results from &gt;90% target suppression and is observed with 30 mg/kg once daily dosing. Furthermore, in non-clinical toxicology studies, projected human efficacious exposures were well tolerated. With potent activity against PDGFRα D842V and KIT Exon 17 mutants, BLU-285 targets previously unaddressed genomic drivers of disease and provides promise for the treatment of PDGFRα D842V-driven GIST or SM, where more than 90% of patients carry the KIT D816V mutation. Besides single agent activity, the highly selective BLU-285 offers an opportunity for combination with other agents in GIST to cover the entirety of KIT primary and resistance mutants. This approach of pairing potent, selective kinase inhibitors with defined disease-driving kinase mutants is designed to fulfill the promise of personalized medicine and, if clinically proven, may provide maximum benefit to patients. BLU-285 is scheduled to enter first-in-human phase 1 clinical trials for both the GIST and SM patient populations in the first half of 2015.
Citation Format: Erica K. Evans, Brian L. Hodous, Alexandra K. Gardino, Alison Davis, Julia Zhu, Adam Shutes, Joseph L. Kim, Kevin J. Wilson, Doug Wilson, Yulian Zhang, Tat Chu, Nancy E. Kohl, Vivek Kadambi, Timothy Guzi, Christoph Lengauer. BLU-285, the first selective inhibitor of PDGFRα D842V and KIT Exon 17 mutants. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 791. doi:10.1158/1538-7445.AM2015-791