Mechanism of Action

Why Aurora A

JAB-2485 is a highly selective, small-molecule inhibitor of AURKA. AURKA plays an important and crucial role in cellular division regulating centrosome maturation and appropriate chromosomal segregation. AURKA inhibitors tested over the past decade have demonstrated intolerable toxicity which appears to be due to the off-target effects on the homologous protein AURKB. The development of a highly selective AURKA inhibitor with minimal off-target effects is a considerable advance in the development of this drug class. JAB-2485 potently inhibits AURKA activity without significantly interrupting AURKB activity. This inhibition leads to cell cycle arrest in the G2/M phase, resulting in abnormal mitosis, induction of apoptosis, and ultimately a reduction of tumor cell growth.

RB is an important tumor suppressor gene and RB loss is commonly observed in patients with small cell lung cancer. RB loss results in the constitutive activation of the spindle assembly checkpoint (SAC) complex in tumor cells. This activation creates hyperactive mitosis of tumor cells and promotes rapid tumor growth. Recent studies have shown that tumors with RB loss are highly sensitive to AURKA inhibitors. The targeting of AURKA in tumors with RB loss has a synthetic lethal effect due to the interaction of both genes on mitosis.

Indications

JAB-2485 is intended for the treatment of a variety of solid tumors, including estrogen receptor-positive (ER+) breast cancer, triple-negative breast cancer, small cell lung cancer and solid tumors with mutations in the ARID1A (AT-rich structural domain 1A) gene. The incidence of these cancers is significant, and although there are effective options for some patients, most will eventually undergo resistance and rapid disease progression following chemotherapy. JAB-2485 has the potential to bring additional treatment options for these patients and fill a highly unmet medical need.

Clinical Trial

 

Asset
Programs
Region
Phase
Indication
Registration information
          
JAB-2485
Mono and Combo w/ PD-1 mAb
U.S. and China
I/IIa
Advanced Solid Tumors
NA

References

  • Cancer Discov. 2019 Feb;9(2):248-263. doi: 10.1158/2159-8290.CD-18-0469. Epub 2018 Oct 29.
  • Cell Death Dis. 2019 Nov 21;10(12):881. doi: 10.1038/s41419-019-2120-1.