Reference Detail

Ref Type

Abstract

PMID

Authors

Jessica Casaletto, Dejan Maglic, B. Barry Toure, Alex Taylor, Heike Schoenherr, Brandi Hudson, Kamil Bruderek, Songping Zhao, Patrick O'Hearn, Nastaran Gerami-Moayed, Demetri Moustakas, Roberto Valverde, Lindsey Foster, Hakan Gunaydin, Pelin Ayaz, Dina Sharon, Donald Bergstrom and James Watters

Title

RLY-4008, a novel precision therapy for FGFR2-driven cancers designed to potently and selectively inhibit FGFR2 and FGFR2 resistance mutations

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer Research	81	13_Suppl	2021

URL

https://cancerres.aacrjournals.org/content/81/13_Supplement/1455.short

Abstract Text

FGFR2 fusions, amplifications, and mutations are oncogenic drivers that occur across multiple tumor types. Clinical efficacy observed with pan-FGFR inhibitors has validated the driver status of FGFR2 in FGFR2 fusion-positive intrahepatic cholangiocarcinoma (ICC), however, FGFR1-mediated toxicities (hyperphosphatemia, tissue mineralization) and the emergence of on-target FGFR2 resistance mutations limit the efficacy of pan-FGFR inhibitors. To overcome these limitations, we designed RLY-4008, a potent and highly selective, FGFR2 inhibitor. Despite significant investment in traditional structure-based drug design, selective targeting of FGFR2 has not been achieved. We leveraged differences in conformational dynamics between FGFR2 and other FGFR isoforms observed through molecular dynamics simulations to enable the design of RLY-4008. RLY-4008 inhibits FGFR2 with low nanomolar potency and demonstrates > 200-fold selectivity over FGFR1, and > 80- and > 5000-fold selectivity over FGFR3 and FGFR4, respectively, in biochemical assays. Additionally, RLY-4008 demonstrates high kinome selectivity for FGFR2 against a panel of > 400 human kinases. RLY-4008 has strong activity against primary and acquired FGFR2 resistance mutations in cellular assays, and potent antiproliferative effects on FGFR2-altered human tumor cell lines. In vivo, RLY-4008 demonstrates dose-dependent FGFR2 inhibition and induces regression in multiple human xenograft tumor models, including FGFR2 fusion-positive ICC, gastric, and lung cancers, FGFR2-amplified gastric cancer, and FGFR2-mutant endometrial cancer. Strikingly, RLY-4008 induces regression in an FGFR2 fusion-positive ICC model harboring the FGFR2V564F gatekeeper mutation and an endometrial cancer model harboring the FGFR2N549K mutation, two mutations that drive clinical progression on current pan-FGFR inhibitors. In the FGFR2V564F model, pan-FGFR inhibitors are ineffective, even at maximally tolerated doses. Notably, treatment of these tumors with RLY-4008 induces rapid regression and restores body weight. In rat and dog toxicology studies, RLY-4008 is well tolerated and is not associated with hyperphosphatemia or tissue mineralization at exposures significantly above those required to induce regression in all models. In contrast to pan-FGFR inhibitors, RLY-4008 is highly selective for FGFR2 and demonstrates strong activity against FGFR2 resistance mutations, suggesting that RLY-4008 may have broader therapeutic potential via preventing and overcoming therapeutic resistance. Together, these data and the favorable pharmaceutical properties of RLY-4008 strongly support its clinical development in FGFR2-altered tumors.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR2 N549K	endometrial cancer	predicted - sensitive	RLY-4008	Preclinical - Cell culture	Actionable	In a preclinical study, RLY-4008 treatment led to tumor regression in a cell line xenograft model of endometrial cancer harboring FGFR2 N549K (Cancer Res 2021;81(13_Suppl):Abstract nr 1455).	detail...