TG02: A novel, multi-kinase inhibitor with potent activity against solid tumors.

Abstract

e13549 Background: Kinase inhibitors have found applications in oncology due to their ability to target key signaling pathways in many different cancers. In general, broad-spectrum kinase inhibitors have yielded better clinical outcomes than more selective ones because they block more than one pathway critical for tumor growth. We describe herein the pharmacological profile of TG02, a multi-kinase inhibitor being developed by Tragara Pharmaceuticals, which combines cell cycle regulatory and transcriptional CDK inhibition with activity against kinase targets involved in antiapoptotic signaling and other aspects of the malignant phenotype. Methods: In vitro potency was evaluated using kinase assays, Western blot analyses of the pathway components, FACS-based cell cycle analyses and proliferation and apoptosis assays in human tumor lines. Evaluation of in vivo PK, PD biomarkers and antitumor efficacy was in nude mouse xenograft models of solid tumors. Results: TG02 was shown to be a 10-50nM inhibitor of CDKs 1,2,7 and 9 and other ongogenic kinases, including FLT3, JAK2 and ERK5. TG02 potently inhibits proliferation across a broad panel of human solid tumor cell lines (n = 15, IC50 from 64 to 504 nM). This potency exceeded that of other pan-CDK inhibitors currently in clinical development (SNS-032 and seliciclib) and other drugs that block FLT3 and JAK2 but lack CDK activity (sunitinib and TG101348), suggesting that the unique spectrum of kinases inhibited by TG02 may provide enhanced antitumor activity in solid tumors. TG02 potently induced G2/M cell cycle arrest that rapidly progressed to robust apoptosis in HCT116 cells and synergized with doxorubicin in pancreatic and breast cancer cell lines and with gemcitabine in ovarian carcinoma cells. TG02 was cleared from the blood within 8 hours of PO dosing but was retained in tumor masses at supratherapeutic levels for 24-48 h, depending on dose. Accordingly, pathway-related biomarkers were markedly suppressed for 24-72 h after dosing. In mice bearing SC HCT116 xenografts, TG02 inhibited tumor growth by 82% (p<0.001) at 75 mg/kg PO Q2D. Conclusions: TG02 is a multi-kinase inhibitor with a previously unreported spectrum of targets that shows promising preclinical activity for the treatment of solid tumors in man. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration S*BIO Pte Ltd, Tragara Pharmaceuticals S*BIO Pte Ltd, Tragara Pharmaceuticals