BlackSwan Pharma announced today exciting news concerning its development candidate CD-160130 resulting from its recent collaboration with Professor Annarosa Arcangeli of the Department of Experimental Pathology and Oncology at the University of Florence (Italy). Previously BlackSwan Pharma reported that CD-160130 may exert its apoptotic actions on B lymphocytic leukaemia cells through a novel ion channel action.  

Through the pioneering work of Professor Arcangeli, renowned worldwide for her work in the field of ion channels and cancer, her group was the first to discover the presence of alternative splicing products of the herg1 gene. Some types of tumour cells, mainly neuroblastomas and leukemias, express an alternative transcript of the herg1 gene, named herg1b, whose protein product (hERG1B) has a deleted N-terminus. In the human heart although herg1b is expressed,  herg1a is by and large the major form still found.  In contrast to this,  the herg1b transcript often predominates  in tumour cells where hERG1B proteins forms heterotetramers together with hERG1A,  thus dictating the biophysical features of the resulting current.  Interference with the cardiac-type hERG1 channel is seen by the pharmacological industry as a serious barrier to any drug development.  Now this discovery by Professor Ancangeli has given rise to an important concept that selective inhibition of this tumour cell hERG channel may represent a new therapeutic approach to cancer therapy.

In line with Professor Arcangeli´s previous observations, her group studied the effects of CD-160130 using various cell lines that express the different hERG channels.  Tested on HEK 293 cells transfected with the cardiac-type hERG1A subunit, CD-160130 was able to reduce potassium currents with an IC50 of 13 µM.   In comparison, using the human neuroblastoma cell line, SH-SY5Y, and a human myeloid leukemia cell line, FLG 29.1, cell lines preferentially expressing the hERG1B isoform, CD-160130 demonstrated 6-fold more potency, and hence selectivity, in inhibiting potassium currents. Further evidence for this selective effect of CD-160130 on the “tumour-type” hERG1 channel was elegantly shown by Professor Arcangeli´s group who transfected HEK293 cells with the hERG1B isoform and then compared the inhibitory effect of CD160130 on HEK 293-hERG1A and HEK 293-hERG1B after applying the same electrophysiological stimulus.  Their data demonstrated CD-160130 to reduce potassium channel activity in the HEK 293-hERG1B cells at concentrations similar to that obtained in the tumour cells used previously.

These findings demonstrate for the first time that selective inhibition of hERG1 channel isoforms can be achieved and may represent an important milestone since the targeting of hERG1 in tumour cells can be seen as a means to both induce apoptosis and also to overcome the resistance to classical chemotherapeutic drugs used for the treatment of leukaemias. 

CD160130 can be seen as the first therapeutic agent to be under development as a selective tumour hERG channel inhibitor.