First-in-class oral small molecule inhibitor of the tyrosine kinase ROR1 (KAN0439834) induced significant apoptosis of chronic lymphocytic leukemia cells

Hojjat‐Farsangi, Mohammad; Daneshmanesh, Amir Hossein; Khan, Abdul Salam; Shetye, Jayant; Mozaffari, Fariba; Kharaziha, Pedram; Rathje, Li-Sophie Zhao; Kokhaei, Parviz; Hansson, Lotta; Vågberg, Jan; Byström, Styrbjörn; Olsson, Eva; Löfberg, Charlotta; Norström, Carina; Schultz, Johan; Norin, Martin; Olin, Thomas; Österborg, Anders; Mellstedt, Håkan; Moshfegh, Ali

doi:10.1038/s41375-018-0113-1

Cited by 35 publications

(54 citation statements)

References 13 publications

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“…SUDHL4 (GCB type) ROR1 + ; MS (GCB type) ROR1 + ; RC-K8 (GCB type) ROR1 + ; OCI-LY3 (ABC type) ROR1 + ; U2932 (ABC type) ROR1 − . ROR1 expression was analyzed by flowcytometry and Western blot (see below) including expression of phosphorylated ROR1 protein (pROR1) [29]. Cells were cultured in RPMI-1640 medium (Life Technologies, Karlsruhe, Germany), supplemented with 10% fetal calf serum (Life Technologies), penicillin (100 IU/mL) and streptomycin (100 µg/mL) (Life Technologies).…”

Section: Cell Linesmentioning

confidence: 99%

“…The development of the first small molecule inhibitor of the tyrosine kinase ROR1 (KAN0439834) was recently described [29]. Following a high-throughput screening campaign against the tyrosine kinase domain of ROR1, more than 2000 compounds were synthesized in the hit-to-lead and lead optimization stages.…”

Section: Small Molecule Ror1 Tyrosine Kinase Inhibitors (Kan0439834 Amentioning

confidence: 99%

“…We recently described a first-in-class ROR1 small molecule inhibitor (SMI) (KAN0493834) inducing specific apoptosis of CLL cells and tumor cell reduction in immunodeficient mice xenotransplanted with human CLL cells [29]. Our ROR1 SMI shows binding to ROR1, dephosphorylation of ROR1 [29] and in silico modeling high fitting of the SMI to the ATP pocket of the TK domain [29].…”

Section: Introductionmentioning

confidence: 99%

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ROR1 is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells

et al. 2020

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The receptor tyrosine kinase ROR1 is absent in most normal adult tissues, but overexpressed in several malignancies. In this study, we explored clinical and functional inhibitory aspects of ROR1 in diffuse large B-cell lymphoma (DLBCL). ROR1 expression in tumor cells was more often observed in primary refractory DLBCL, Richter’s syndrome and transformed follicular lymphoma than in relapsed and non-relapsed DLBCL patients (p < 0.001). A survival effect of ROR1 expression was preliminarily observed in relapsed/refractory patients independent of gender and stage but not of age, cell of origin and international prognostic index. A second generation small molecule ROR1 inhibitor (KAN0441571C) induced apoptosis of ROR1+ DLBCL cell lines, similar to venetoclax (BCL-2 inhibitor) but superior to ibrutinib (BTK inhibitor). The combination of KAN0441571C and venetoclax at EC50 concentrations induced almost complete killing of DLBCL cell lines. Apoptosis was accompanied by the downregulation of BCL-2 and MCL-1 and confirmed by the cleavage of PARP and caspases 3, 8, 9. PI3Kδ/AKT/mTOR (non-canonical Wnt pathway) as well as β-catenin and CK1δ (canonical pathway) were inactivated. In zebra fishes transplanted with a ROR1+ DLBCL cell line, KAN0441571C induced a significant tumor reduction. New drugs with mechanisms of action other than those available for DLBCL are warranted. ROR1 inhibitors might represent a novel promising approach.

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Section: Cell Linesmentioning

confidence: 99%

Section: Small Molecule Ror1 Tyrosine Kinase Inhibitors (Kan0439834 Amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ROR1 is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells

et al. 2020

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“…In addition to cirmtuzumab, a number of other anti-ROR1 therapies are also in pre-clinical development Ca, cancer; CLL, chronic lymphocytic leukaemia; Endo, endometrial; met, metastatic; SC, squamous cell; TNBC, triple-negative breast cancer. (Hojjat-Farsangi et al 2017, Yin et al 2017, Hassannia et al 2018. Of these, ROR1 chimeric antigen receptor (CAR)-T cell therapy has attracted interest.…”

Section: :12mentioning

confidence: 99%

An update of Wnt signalling in endometrial cancer and its potential as a therapeutic target

Coopes

Henry

Llamosas

et al. 2018

Endocrine-Related Cancer

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Endometrial cancer is the most common gynaecological malignancy in developed nations, and its prevalence is rising as women defer or decide not to have children and as obesity rises, both key risk factors. Despite this, treatment options remain limited, particularly for advanced or refractory disease. New genomic analyses have revealed distinct mutational profiles with therapeutic and prognostic potential. Wnt signalling, which is pivotal in embryogenesis, healing and homeostasis, is of importance in the endometrium and has been linked to carcinogenesis. This review aims to update and discuss the current evidence for the role of β-catenin dependent and independent Wnt signalling, including the ROR receptors in the endometrium and its potential as a therapeutic target, in light of recent trials of Wnt-targeted therapy in multiple tumour types.

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“…CLL, mantle cell lymphoma, B-cell ALL) and numerous types of solid tumors (37)(38)(39)(40). Due to its high-level surface expression as well as to its crucial role in tumor cell proliferation, survival, and metastasis, a number of pharmacological agents targeting ROR1 are under development, such as humanized monoclonal antibodies, small molecule inhibitors, bispecific T-cell engagers (BiTE) and anti-ROR1 CAR T cells (41)(42)(43). ROR1-targeted T cells have demonstrated to generate cytotoxicity against human ROR1 positive B cell malignancies in preclinical studies (39), without causing overt cytotoxicity in nonhuman primates (44).…”

Section: Novel T-cell Targets For B-cell Malignanciesmentioning

confidence: 99%

Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives

Coscia¹

2019

Front Biosci

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First-in-class oral small molecule inhibitor of the tyrosine kinase ROR1 (KAN0439834) induced significant apoptosis of chronic lymphocytic leukemia cells

Cited by 35 publications

References 13 publications

ROR1 is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells

ROR1 is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells

An update of Wnt signalling in endometrial cancer and its potential as a therapeutic target

Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives

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