Abstract A123: Delivery of a potent, selective, and efficacious RET inhibitor for the treatment of RET-driven lung adenocarcinoma
Authors: Watson Mandy , Newton Rebecca , Acton Ben , Small Helen , Begum Habiba , Hitchin Samantha , Kelly Paul , Ogilvie Donald , Waddell Ian , Jordan Allan 
Published: August 2018

Abstract
Background: Constitutive activation of RET kinase activity following mutation or rearrangement can lead to the development of cancers such as medullary thyroid carcinoma and lung adenocarcinoma. The currently approved therapeutics for these diseases are significantly compromised due to dose-limiting toxicities associated with off-target activity vs KDR (VEGFR2) and lack of potency vs anticipated secondary resistance (e.g., gatekeeper) mutations. Consequently there is considerable interest in the development of highly selective inhibitors targeting diverse RET alterations including the putative resistance mutation, V804M. Methods: We have established a robust screening cascade complemented by structure-enabled drug design and effective medicinal chemistry. Biochemical activity vs RET, KDR, and RETV804M protein was assessed using a HTRF assay. Cellular activity was quantified in BaF3 cells dependent on activity of RET, KDR, or RETV804M for proliferation. Tumor growth inhibition and supporting PK/PD studies were carried out in a number of disease-relevant models including a KIF5B-RET lung cancer patient-derived xenograft (PDX) model, a medullary thyroid carcinoma (MZ-CRC-1) xenograft model, and a lung cancer control (Calu-6) xenograft model. Results: Using this optimized, robust platform, we have identified a number of selective compounds offering a range of interesting biochemical and cellular profiles, targeting either, or both, RET and the gatekeeper mutant, RETV804M. We believe certain examples of these compounds offer the first cell-active RETV804M-selective derivatives. More importantly perhaps, we have also delivered a highly selective preclinical candidate compound demonstrating potency vs both RET fusion and RETV804M. This compound is well tolerated in vivo after oral dosing at up to 80mg/kg bid and, in a KIF5B-RET lung cancer PDX model, demonstrates efficacy at much lower doses: 50% tumor regression at 20mg/kg bid and 92% tumor growth inhibition at 10mg/kg bid. Importantly, this agent shows no efficacy in the (non-RET driven) Calu-6 xenograft model, demonstrating selective inhibition of the RET kinase domain. Conclusions: We believe that the identification of well-tolerated, selective RET inhibitors with potent activity against diverse RET alterations (including the anticipated resistance mutation, V804M) offers a clear therapeutic advantage over the present clinically approved compounds. Our most advanced compound fulfills all of these challenging criteria and has now entered preclinical development.
Citation Format: Mandy Watson, Rebecca Newton, Ben Acton, Helen Small, Habiba Begum, Samantha Hitchin, Paul Kelly, Donald Ogilvie, Ian Waddell, Allan Jordan. Delivery of a potent, selective, and efficacious RET inhibitor for the treatment of RET-driven lung adenocarcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A123.