Pipeline of first-in-class ADCs
We are progressing a pipeline of proprietary differentiated ADCs based on our novel N-myristoyltransferase inhibitor (NMTi) payload chemistry platform to address serious unmet needs in oncology.
Based on compelling pre-clinical efficacy and safety data across multiple solid tumour associated antigens and cancer cell types we are prioritizing three proprietary, differentiated NMTi-ADCs that target the cancer associated antigens: Trop2, B7-H3 and HER 2.
Delivering NMTis as a new therapeutic payload class
Our novel ultrapotent NMTis are selectively cytotoxic in multiple cancer cell lines as well as exhibiting tumour regression in in vivo models of both haematological and solid cancers. Myricx has also developed a transcriptional signature which predicts with high confidence cancer cell sensitivity to NMTi.
Currently over 95% of ADC warheads/payloads comprise traditional chemotherapeutics such as tubulin binders, Topoisomerase 1 inhibitors or DNA intercalating/damaging agents, but they have limitations due to their broad cytotoxicity.
Unlike traditional payloads NMTis provide several advantages to ADCs, including:
- Intrinsic cancer selectivity whilst being not broadly cytotoxic.
- Unique dual targeting mechanisms due to the combination of an antigen targeting monoclonal antibody (mAb) with delivery to selective cancer cells that have a high sensitivity to NMTi.
NMTi – new biology reveals a unique mechanism of action that targets cancer cell killing
Combining our highly potent and selective small molecule inhibitors of NMT as tools with system-level analysis of hundreds of cancer cell lines, we have achieved breakthrough discoveries that identified that inhibition of NMT results in cancer cell killing via an unexpected and unique mechanism.
Proof of concept (PoC) and pre-clinical studies
Myricx’s initial PoC ADC studies focused on MYX2449, a selective and ultrapotent NMTi payload conjugated to Ttrastuzumab (HER2+ monoclonal antibody) via a clinically validated lysosomal cleavable linker.
Positive in vitro and in vivo data demonstrated MYX2449 cytotoxic potency in antigen positive cancer cell lines, anti-tumour efficacy in both high and moderate HER2 expressing cancers, with tolerability >10 times its efficacious dose in in vivo models.
MYX2449 was tested using in vivo models of HER2 positive gastric cancer (GC) and breast cancer (BC), MYX2449 delivered improved efficacy compared to the gold standard ADC trastuzumab-deruxtecan in an NCI-N87 GC model.
Similar efficacy was obtained in a BC xenograft model.
To learn more on NMTi payloads and PoC data view our AACR 2023 poster
NMTi discovery – IMP-1088
Myricx’s collaborative team established a new series of human NMT inhibitors discovered through a novel fragment reconstruction approach that used a high-throughput screen to test small-molecule inhibitors that they had previously developed against NMT enzymes from pathogenic fungi and parasites. It was reasoned that if they could find an existing molecule with low affinity for the human NMT enzymes, they could then optimise it.
As predicted, they identified two small-molecule inhibitor fragments of NMT from Plasmodium falciparum, the protozoan parasite which causes malaria. Cooperative binding between these weak-binding fragments was shown which led to rapid inhibitor optimisation through fragment reconstruction, structure-guided fragment linking and conformational control over linker geometry. This optimisation process was monitored via x-ray crystallography, until the new inhibitor fit closely into the human NMT‘s active site. The resulting lead compound in the series – IMP-1088 – is more than 100 times as potent as the starting molecules from which it was built (Mousinier et al 2018 Nat Chem).
NMTi – small molecule drug programmes
NMT inhibitors (NMTi) have been shown to inhibit viability and growth of haematological cancers. We have developed novel highly potent and selective NMTi which are highly efficacious in multiple cell lines as well as exhibit tumour regression in in vivo models. Myricx has identified both IV and oral candidates that have completed non-GLP rat and dog repeat dose tox studies.
