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Abbisko presented two preclinical research results at the 35th International Molecular Targets and Cancer Treatment Conference (EORTC-NCI-AACR)


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Abbisko

Oct 16, 2023, 06:20 ET

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SHANGHAI, Oct. 16, 2023 /PRNewswire/ -- Abbisko Therapeutics Co., Ltd. ("Abbisko" hereafter) announced that the results of the company's two preclinical studies published at the 35th International Molecular Targets and Cancer Treatment Conference (EORTC) be held in Boston, U.S.. These two research results respectively demonstrate the latest preclinical research progress of the next generation of PRMT5*MTA inhibitors and small molecule brain penetrant PD-L1 inhibitors in Abbisko's pipeline. As the world's highest-quality research conference focusing on molecular targeting and tumor treatment, the ENA conference collects the most cutting-edge researches on innovative drugs and therapies in the field of tumor treatment.

Abbisko presented the following posters at the ENA conference:

Title: Discovery and characterization of an MTA-cooperative and brain-penetrant PRMT5 inhibitor

Poster number: C130

Session date and time: Saturday, October 14 | 12:30 pm-4:00 pm

Session location: Level 2, Exhibit Hall D

Background: MTAP is homozygous deleted in ~50% in glioblastoma and many other cancers. PRMT5*MTA inhibition has been shown to be synthetic lethal with MTAP deletion. First generation PRMT5 inhibitors could not distinguish between PRMT5*MTA or PRMT5 alone, thus limited by their shallow therapeutic windows in clinical use. Development of selective PRMT5*MTA inhibitors may improve not only safety but also therapeutic efficacy. Leveraging advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a potent and selective MTA-cooperative and brain-penetrable PRMT5 inhibitor ABK-PRMT5-1, which demonstrates strong anti-tumor activity and brain-penetrating activity in various preclinical models.

Conclusion:

ABSK-PRMT5-1 strongly inhibits cell proliferation in MTAP-deleted cancer cell lines, with minimal effects on MTAP wildtype cell lines. Furthermore, it significantly reduces SDMA in MTAP-deleted cancer cell lines. Oral administration of ABSK-PRMT5-1 strongly inhibits tumor growth in MTAP-deleted xenograft tumor models. In addition, ABSK-PRMT5-1 demonstrates strong brain penetration with excellent Kp values in animals. DMPK and safety profiling shows good overall drug-like properties of ABK-PRMT5-1. ABK-PRMT5-1, presented here by Abbisko Therapeutics, is a highly selective MTA-cooperative and brain-penetrable PRMT5 inhibitor. Its superior profile supports fast-track preclinical development.

Title: Discovery and characterization of a novel small molecule brain penetrant PD-L1 inhibitor

Poster number : B151

Session date and time: Friday, October 13 | 12:30 pm-4:00 pm

Session location: Level 2, Exhibit Hall D

Background: Immunotherapy has revolutionized cancer treatment in the last decade. Several monoclonal PD-1 and PD-L1 antibodies have been approved for treating various cancers. Small molecule PD-L1 inhibitors with brain-penetrating ability may have potential to overcome the limitations of antibodies and bring benefit for patients with intracranial tumors. Leveraging advanced computation-aided structural analysis and medicinal chemistry design, we have successfully discovered an innovative orally available small molecule PD-L1 inhibitor ABSK044. In preclinical experiments, this compound demonstrates robust T-cell activating ability, strong anti-tumor efficacy, and brain-penetrating activity.

Conclusion:

ABSK044 strongly inhibits PD-1-PD-L1 interaction with an IC50 less than 1nM in vitro and very potently rescues PD-L1-induced suppression of T cell activation signaling in cells. Furthermore, it efficiently rescues cytokine production in CD8+ T cells suppressed by PD-L1, reaching a level comparable to that of PD-L1 antibodies. In in vivo studies, oral administration of ABSK044 strongly inhibits tumor growth to an extent similar to therapeutic anti-PD-L1 antibodies. Notably, ABSK044 demonstrates excellent brain penetration with a Kp value exceeding 0.4. DMPK and safety profiling demonstrate excellent drug-like properties of ABSK044.

ABSK044, presented here by Abbisko Therapeutics, is a highly potent and orally available small molecule PD-L1 antagonist with brain-penetrating activity. Its superior profile supports its fast-track preclinical development.

SOURCE Abbisko

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