1533P - First generation of a small chemical molecule ROR1 RTK tyrosine kinase inhibitor

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Translational Research
Presenter Håkan Mellstedt
Citation Annals of Oncology (2016) 27 (6): 526-544. 10.1093/annonc/mdw392
Authors H. Mellstedt1, M. Hojjat-Farsangi2, A.H. Daneshmanesh3, A. Moshfegh3, S. Byström4, M. Norin4, T. Olin4, J. Schultz4, J. Vågberg4, A. Österborg5
  • 1Dept Of Oncology-pathology, Karolinska Institute, S-171 76 - Stockholm/SE
  • 2Department Ofoncology-pathology, Karolinska Institute, SE-171 76 - Stockholm/SE
  • 3Department Of Oncology-pathology, Karolinska Institute, SE-171 76 - Stockholm/SE
  • 4-, Kancera AB, SE-171 48 - Stockholm/SE
  • 5Department Of Hematology, Karolinska University Hospital Solna, SE-171 76 - Stockholm/SE

Abstract

Background

The receptor tyrosine kinase (RTK) ROR1 is of importance during embryogenesis for the central nervous, musco-skeletal and cardio-pulmonary systems. ROR1 is practically not present in normal adult tissues. ROR1 is however re-expressed in several hematological and non-hematological malignancies and involved in tumor cell proliferation, survival, invasiveness and metastases. The unique characteristics of this onco-fetal RTK should make it a suitable candidate for targeted therapy.

Methods

A chemical synthesis program has been initiated based on a chemical library and phenotypic screening programme. Small molecules have been produced which specifically target the phosphorylated TK domain of ROR1. Tumor cell death in vitro is measured by Annexin V/PI and MTT. Effects on signaling molecules by WB for phosphorylated and non-phosphorylated proteins. Xenotransplanted non-scid mice and zebra fishes are used for in vivo testing of anti-tumor effects.

Results

Phosphorylated ROR1 is expressed in e.g. CLL, triple negative breast cancer, pancreatic and lung cancer cells. A lead compound has been synthesized, KAN 0439834. In biochemical assay IC50 is 5 nM. The compound kills specifically with high efficiency chronic lymphocytic leukemia cells, triple negative breast cancer cells, pancreatic carcinoma cells, lung cancer cells. The ligands for ROR1 is Wnt5a and 3a which both are expressed in tumor cells. The drug specifically dephosphorylated ROR1 as well as downstream Wnt canonical (e.g. GSK3ß) and non-canonical (e.g. PI3K, AKT, mTOR) molecules. In non-scid mice transplanted with human CLL cells a significant reduction of CLL cells was noted as well as inhibition in the zebra fish model of triple negative breast cancer cells of tumor growth and metastases. KAN 0439834 is well tolerated in the mice.

Conclusions

ROR1 is an activated onco-fetal RTK expressed in various malignancies. Small chemical molecules specifically targeting ROR1 could be shown in vitro and in vivo preclinical models to specifically and efficiently kill tumor cells at a low concentration. The oral available KAN 0439834 is the first generation of a ROR1 TKI with promising characteristic to be further developed for first-in-man clinical trials.

Clinical trial identification

Not applicable.

Legal entity responsible for the study

Karolinska Institute, Department of Oncology-Pathology and Department of Hematology.

Funding

Kancera AB, Karolinska Institute Science Park

Disclosure

H. Mellstedt: Co-founder of Kancera AB and member of Board of Directors as well as stock owner. M. Hojjat-Farsangi, A.H. Daneshmanesh, A. Österborg: Stock owner of Kancera AB. A. Moshfegh: Employee and stock owner at Kancera. S. Byström, M. Norin, T. Olin, J. Schultz, J. Vågberg: Employee and stock owner at Kancera.