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Disease Domain	Count

Endocrinology and Metabolic Disease	1
Immune System Diseases	1
Neoplasms	1

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Small molecule drug	3

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ROCK(Rho-associated kinases)	1
PORCN(Protein-serine O-palmitoleoyltransferase porcupine)	1
DDR1(Discoidin domain receptor 1)	1

Gastrointestinal cancers are responsible for more cancer deaths than any other system of the body. This review summarises how Wnt pathway dysregulation contributes to the development of the most common gastrointestinal cancers, with a particular focus on the nature and frequency of upstream pathway aberrations. Tumors with upstream aberrations maintain a dependency on the presence of functional Wnt ligand, and are predicted to be tractable to inhibitors of Porcupine, an enzyme that plays a key role in Wnt secretion. We summarise available pre-clinical efficacy data from Porcupine inhibitors in vitro and in vivo, as well as potential toxicities and the data from early phase clinical trials. We appraise the rationale for biomarker-defined targeted approaches, as well as outlining future opportunities for combination with other therapeutics.

03 Dec 2015·Blood

Development of REDX05194, a Novel, Potent and Selective Inhibitor of Bruton's Tyrosine Kinase (BTK) As a Potential Treatment for B-Cell Malignancies

Author: Talab, Fatima ; Proctor, Lauren ; Ho, Kelvin ; Emmerich, Juliette ; Bingham, Matilda ; Best, Stuart ; Harmon, Shona ; Calder, Mathew ; Guisot, Nicolas E S ; Armer, Richard ; Lucas, Catherine L ; Muller, Melanie ; Refuerzo, Julienne ; Campbell, Mary-Ann ; Walker, Victoria ; Chappell, Rose

AbstractThe B-cell receptor (BCR) signaling pathway is required for the survival, activation, proliferation and differentiation of B-cells. Bruton's Tyrosine Kinase (BTK) is a member of the Tec protein tyrosine kinase family that has emerged as an attractive target for the treatment of B-cell malignancies due to the critical role it plays in BCR signaling. Redx Oncology has developed novel differentiated small molecule inhibitors of BTK, combining current best-in-class potency with distinct selectivity profiles, which are suitable for oral once daily dosing. Here we present REDX05194, the result of a successful lead optimization of our proprietary BTK inhibitor series.REDX05194 is a highly selective, covalent BTK inhibitor displaying subnanomolar binding affinity for BTK (0.39 nM) and nanomolar potency towards BTK in a biochemical assay (3.67 nM). In cell proliferation assays, REDX05194 showed significant in vitro potency against ABC-DLBCL cell lines inhibiting the growth of both TMD-8 (0.89 nM) and OCI-Ly10 (1.36 nM) cells. Analysis of BCR signaling in several lymphoma cell lines, including cell lines of ABC-DLBCL, MCL and FL origin, revealed that treatment with REDX05194 inhibits BTK autophosphorylation and downstream activation of PLCγ2. In human PBMCs, REDX05194 inhibited anti-IgM stimulated upregulation of the CD69 activation marker in CD19 positive B-cells. In addition, using a fluorescent probe that binds to BTK, occupancy of BTK in PBMCs has been demonstrated in response to increasing concentrations of REDX05194.To assess selectivity, 456 kinases were screened at 1 μM, confirming that REDX05194 does not significantly inhibit other kinases involved in BCR signaling (e.g. Syk, Lyn). Furthermore, REDX05194 was shown to have high selectivity versus structurally related cysteine-containing kinases such as ITK in binding assays, and EGFR as demonstrated in both binding and cellular assays. REDX05194 also has a favorable in vitro safety profile and drug-like properties, displaying an improved CYP profile and solubility compared to competitor compounds.REDX05194 demonstrated in vivo efficacy in a mouse collagen-induced arthritis (CIA) model. At 10 mg/kg and 30 mg/kg QD, REDX05194 significantly improved all clinical readouts, including disease severity, compared to the vehicle group. Histological data showed that approximately 1/3 of the mice had no or minimal pannus infiltration and no bone resorption, or had bone resorption restricted to small areas. These findings demonstrate potential clinical efficacy and a dose response.In conclusion, REDX05194 is a highly selective and potent BTK inhibitor with proven efficacy in several lymphoma cell lines and human PBMCs and in vivo efficacy demonstrated in a mouse CIA model.DisclosuresNo relevant conflicts of interest to declare.

100 Deals associated with Redx Oncology Ltd.

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100 Translational Medicine associated with Redx Oncology Ltd.

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Pipeline

Pipeline Snapshot as of 05 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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2

1

Phase 2 Clinical

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2

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

Zamaporvint ( PORCN )	Pancreatic Cancer More	Phase 2
Discoidin Domain Receptor Inhibitors(Redx Pharma) ( DDR1 )	Fibrosis More	Preclinical
RXC-008 ( ROCK )	Crohn Disease More	Preclinical
RXC-001 ( SMO )	Basal Cell Carcinoma More	Pending
REDX-05194 ( BTK )	Neoplasms More	Pending