57 and 59 and CARM1, clearly revealing the expected active site interactions with
the adenosine and guanidine groups.
6.3 Biological Relevance of Inhibitors and Current Outlook
The involvement of CARM1 in a wide range of human cancers has led to increasing
interest in the discovery of a potent and selective CARM1 inhibitor. The first
inhibitors described for CARM1 came from high-throughput screening campaigns
and showed selectivity for CARM1 over PRMT1 and PRMT3 but were not tested
against other PRMTs. Results of later studies showed that structurally similar
compounds were equally active against CARM1 and PRMT6. Both CARM1 and
PRMT6 are involved in a variety of cancers, and synergy between the two has been
described in stimulating oestrogen receptor α-dependent transcription. Dual active
compounds, like MS049, are great tool compounds to investigate this synergy in
detail. TP-064 is the most potent and selective CARM1 inhibitor described to date,
showing activity in enzymatic assays and cell proliferation assays. In addition, the
potent and selective peptidic transition state mimics developed by our group are
valuable tools for structural studies to investigate PRMT-substrate interactions. The
structural information made possible by this approach may yield new insights for the
discovery of new PRMT inhibitors.
Fig. 14 Co-crystal structures of transition state mimics 57 and 59 bound to CARM1 (PDB ID:
5LGP and 5LGQ). (a) Compound 57 consists of residues 447–459 of poly(A)-binding protein-1
(PABP1) linked to adenosine via a fully saturated three-carbon linker; (b) compound 59 consists of
residues 456–466 of PABP1 linked to adenosine via a fully saturated three-carbon linker. The most
important interactions with active site residues have been indicated, including E215 interacting with
the hydroxyls of the ribose and E258/E267 of the double E-loop and His415 of the THW-loop
interacting with the guanidine [141]
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177
the adenosine and guanidine groups.
6.3 Biological Relevance of Inhibitors and Current Outlook
The involvement of CARM1 in a wide range of human cancers has led to increasing
interest in the discovery of a potent and selective CARM1 inhibitor. The first
inhibitors described for CARM1 came from high-throughput screening campaigns
and showed selectivity for CARM1 over PRMT1 and PRMT3 but were not tested
against other PRMTs. Results of later studies showed that structurally similar
compounds were equally active against CARM1 and PRMT6. Both CARM1 and
PRMT6 are involved in a variety of cancers, and synergy between the two has been
described in stimulating oestrogen receptor α-dependent transcription. Dual active
compounds, like MS049, are great tool compounds to investigate this synergy in
detail. TP-064 is the most potent and selective CARM1 inhibitor described to date,
showing activity in enzymatic assays and cell proliferation assays. In addition, the
potent and selective peptidic transition state mimics developed by our group are
valuable tools for structural studies to investigate PRMT-substrate interactions. The
structural information made possible by this approach may yield new insights for the
discovery of new PRMT inhibitors.
Fig. 14 Co-crystal structures of transition state mimics 57 and 59 bound to CARM1 (PDB ID:
5LGP and 5LGQ). (a) Compound 57 consists of residues 447–459 of poly(A)-binding protein-1
(PABP1) linked to adenosine via a fully saturated three-carbon linker; (b) compound 59 consists of
residues 456–466 of PABP1 linked to adenosine via a fully saturated three-carbon linker. The most
important interactions with active site residues have been indicated, including E215 interacting with
the hydroxyls of the ribose and E258/E267 of the double E-loop and His415 of the THW-loop
interacting with the guanidine [141]
PRMT Inhibitors
177