tizaterkib (ATG-017)

P1, N=36, Terminated, Antengene Therapeutics Limited | N=211 --> 36 | Recruiting --> Terminated; The study was terminated based on the internal need to re-prioritization the whole pipeline and phase 1 portfolio.

Equally interesting, tizaterkib was shown to decrease the number of CD45- and CD68-positive immune cells in the mouse cochlea following noise exposure. This study suggests that repurposing tizaterkib and the ERK1/2 kinases' inhibition could be a promising strategy for the treatment of NIHL.

P1, N=211, Recruiting, Antengene Therapeutics Limited | Trial completion date: Dec 2024 --> Jun 2024 | Trial primary completion date: Jul 2024 --> Feb 2024

P1, N=211, Recruiting, Antengene Therapeutics Limited | Trial completion date: Aug 2023 --> Dec 2024 | Trial primary completion date: May 2023 --> Jul 2024

Molecular docking data demonstrates that CAPE shows a higher docking score of -5.35 versus -4.59 to known p38 inhibitor SB203580 as well as a docking score of -4.17 versus -3.86 to known ERK1/2 inhibitor AZD0364...These results suggest that stress induction via serum starvation in HT29 CRC cells leads to the induction of apoptosis and co-ordinated activation of MAPK-HSP pathways. Molecular docking studies support that CAPE could serve as an effective inhibitor to target p38 and MAPK compared to their currently known inhibitors.

This study tested the antitumor effects induced by the combination of ATG-012, a KRAS G12C inhibitor, with SHP2 inhibitor (ET0038), ERK 1/2 kinase inhibitor (ATG-017), mTORC1/2 kinase inhibitor (ATG-008) or XPO1 inhibitor (selinexor), in preclinical tumor models. The in vivo combinations of the drugs were tested in NCI-H358 (non-small cell lung cancer) and Mia-Paca-2 (pancreatic cancer) CDX mouse model. Strong in vivo synergism has been observed for the combination of a Kras (G12C) inhibitor (ATG-012) with a SHP2 inhibitor, ERK 1/2 inhibitor, mTORC1/2 inhibitor or XPO1 inhibitor, suggesting promising clinical therapeutic strategies for cancer patients carrying the KRAS G12C mutation.

The AZD0364 and selumetinib combination also results in significant tumour regressions in multiple KRAS mutant xenograft models. The combination of ERK1/2 and MEK1/2 inhibition thereby represents a viable clinical approach to target KRAS mutant tumours.

However, distinct cell line dependent effects were observed. In conclusion, the combination of AZD0364 and ZSTK474 can exert a synergistic anticancer effect in ALL and AML cells, which is associated with the induction of oxidative stress and the involvement of cellular antioxidant defense mechanisms.

We describe our structure-based design approach leading to the discovery of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364 exhibits high cellular potency (IC50 = 6 nM) and excellent physico-chemical and absorption, distribution, metabolism, and excretion (ADME) properties and has demonstrated encouraging anti-tumour activity in pre-clinical models.