Abstract B182: The novel tyrosine kinase inhibitors UJ26 and UJ30 are active in solid tumor and hematologic cancer cell lines
Authors: Tarantelli Chiara , Gaudio Eugenio , Unzue Andrea , Sledz Pawel , Ekeh Hillarie , Bernasconi Elena , Spriano Filippo , Nevado Cristina , Caflisch Amedeo , Bertoni Francesco 
Published: August 2018

Background: Tyrosine kinase (TK) inhibitors represent the class of targeted antitumoral drugs that has been so far more successful. Here, we present two novel TK inhibitors, UJ26 and UJ30, with antitumor activity in preclinical models of solid tumors and hematologic cancers. Materials and Methods: Biochemical kinase profiling was performed (DiscoverX, CA, USA). Cell lines included in the NCI60 panel and lymphoma cell lines were exposed to increasing doses of UJ26, UJ30, and, as control, to the SRC inhibitor dasatinib for 72 hours. Cell proliferation was evaluated by using MTT assay. In vitro synergy was assessed with the Chou-Talalay combination index (CI): synergism (&lt;0.9), additive (0.9-1.1), antagonism/no benefit (&gt; 1.1). DLBCL RI-1 cells (15x106) were s.c. inoculated in NOD-Scid (NOD.CB17-Prkdcscid/NCrHsd) mice. Tumor size was measured on regular basis and drug treatments with UJ26 and UJ30 both given i.p, at the dose of 100mg/kg started when tumors reached 5 mm in diameter (100 mm3). Results: The two novel kinase inhibitors UJ26 and UJ30 presented broad specificity comparable to that of dasatinib, able to inhibit clinically relevant kinases ABL1, EGFR, FLT3, KIT, and MET.

UJ26 and UJ30 presented antitumor activity in the NCI60 cell line panel against models of hematologic malignancies and solid tumors, in particular in the K562 leukemia and KM12 colon cancer cell lines (GI50 &lt; 50 nM). Antiproliferative activity of UJ26 and UJ30 was then assessed in 8 B-cell lymphoma cell lines derived from mantle cell lymphoma (MCL) (Jeko1, MAVER1), chronic lymphocytic leukemia (MEC-1, PCL-12), and diffuse large B cell lymphoma (DLBCL) of the activated B cell like (ABC) (RI-1, SU-DHL-2) or of the germinal center B cell (GCB) (VAL, SU-DHL-4). Compounds were active with median IC50s of 600nM (95%C.I. 300-1065nM) and 250nM (95%C.I. 100-1049nM), respectively. Their antitumor activity appeared more potent than dasatinib (median IC50=1325nM, 95%C.I. 100-16625nM), in particular in 3 of the cell lines (MAVER1, SU-DHL-2 and MEC1). UJ26 and UJ30 were evaluated in combination with the BET inhibitor OTX015, exposing the four most sensitive lymphoma cell lines to increasing concentrations of the single compound or of both compounds for 72h. Both the UJ26/OTX015 combination, as well as the UJ30/OTX015 combination, were synergistic in all the cell lines. In vivo experiments showed that UJ26 was very toxic already after the first dose with swelling of the injection area. UJ26-treated mice started to recover after 2 weeks and were not treated any more, and there was no antitumor effect. UJ30 given once every 5 days reduced tumor volume compared to control group (D5, D11, D15; P &lt; 0.05) and was well tolerated. UJ30-treated xenografts were three times smaller than both control and UJ26 groups at the end of the experiment (D15, UJ30 median tumor volume=867, 95%C.I. 600-1267.5). Body weight loss was observed after treatment with compound UJ26 whereas UJ30 showed similar weight growth as in the control group. Experiment was terminated after 2 weeks for vehicle- and UJ26-treated groups (D15) while UJ30-treated mice were sacrificed at day 20. Conclusions: The novel TK inhibitors UJ26 and UJ30 showed preclinical antitumor activity and in particular UJ30 is worth further investigations. CN, AC, FB: co-senior authors.

Citation Format: Chiara Tarantelli, Eugenio Gaudio, Andrea Unzue, Pawel Sledz, Hillarie Ekeh, Elena Bernasconi, Filippo Spriano, Cristina Nevado, Amedeo Caflisch, Francesco Bertoni. The novel tyrosine kinase inhibitors UJ26 and UJ30 are active in solid tumor and hematologic cancer cell lines [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 B182.