August 2, 2023

expert reaction to study on use of small molecule ligand AOH1996 for inhibiting tumour growth in animals

A study published in Cell Chemical Biology looks at the use of a small molecule for selective chemotherapy.

Prof Dorothy Bennett, Director of the Molecular and Clinical Sciences Research Institute, St George’s, University of London (SGUL), said:

“This paper by Gu et al. is interesting for investigating a relatively novel approach to selective targeting of cancer cells, via the protein target PCNA, which functions in resolving clashes between replication of DNA and transcription (reading the code).

The support for the claim in the paper that their lead anti-PCNA agent AOH1996 “kills cancer cells” appears somewhat limited, disappointingly.  Data on cell killing, or else loss of colony-formation (ability to divide), are provided only for 3 human neuroblastoma lines, and show only that some cells per culture were killed, not all.  All other data are on reductions in growth, so not even showing that net culture growth was arrested.  Likewise, tests on implanted human tumours in mice do not show cell killing by AOH1996, but a slowing of tumour growth with 3 tumour types.  For one neuroblastoma, they show a modest increase in mouse survival time where the agent was combined with another drug (a topoisomerase inhibitor), versus the other drug alone.

On the positive side, there appears to be broad evidence here for retardation of growth (in vitro) of many human cancer cell lines of various types by this agent, with little damage to several normal cell types, suggesting that this kind of approach deserves further development.”

‘Small molecule targeting of transcription-replication conflict for selective chemotherapy’ by Long Gu et al. was published in Cell Chemical Biology on Tuesday 1 August 2023.

DOI: 10.1016/j.chembiol.2023.07.001

Declared interests

Prof Dorothy Bennett: “No conflicts.”