Ipatasertib

(GDC-0068, RG7440)

Ipatasertib, an investigational ATP-competitive small molecule currently being studied for its potential to block AKT
Breast
  • Phase
  • I
  • II
  • III
Gastrointestinal
  • Phase
  • I
  • II
  • III
Genitourinary
  • Phase
  • I
  • II
  • III
Gynecologic
  • Phase
  • I
  • II
  • III
Hematology
  • Phase
  • I
  • II
  • III
Lung
  • Phase
  • I
  • II
  • III
Melanoma
  • Phase
  • I
  • II
  • III
Solid Tumor
  • Phase
  • I
  • II
  • III

This compound and its uses are investigational and have not been approved by the US Food and Drug Administration. Efficacy and safety have not been established. The information presented should not be construed as a recommendation for use. The relevance of findings in preclinical studies to humans is currently being evaluated.

Ipatasertib: An AKT inhibitor1

Ipatasertib is an orally administered, ATP-competitive, selective AKT inhibitor. AKT is a key component of the PI3K/AKT pathway. This pathway is dysregulated in many malignancies, often through acquisition of activating mutations in AKT and phosphatidylinositol 3-kinase (PI3K), loss of the tumor suppressor phosphatase and tensin homolog (PTEN), or amplification of AKT and PI3K.1

Some cancer treatments have led to the aberrant activation of the PI3K/AKT pathway, which resulted in the survival and proliferation of tumor cells.1-4 In various preclinical models, PI3K/AKT/mammalian target of rapamycin (mTOR) signaling was shown to become activated following chemotherapy or antihormonal therapy.3,4

Ipatasertib is designed to target and bind to the adenosine triphosphate (ATP)-binding pocket of the 3 activated isoforms of AKT, potentially inhibiting downstream signaling.1 Ipatasertib is being investigated in combination with various treatment modalities (eg, antihormonal therapy, chemotherapy).1,4

 

1 Ipatasertib is an oral, investigational small molecule currently being studied for its potential to inhibit all 3 isoforms of AKT.1,5 Aberrant AKT signaling is associated with resistance to apoptosis and increased cell growth, proliferation, and metabolism.1-3

The PI3K/AKT signaling pathway

 

Ipatasertib is designed to bind to the ATP-binding pocket of the 3 isoforms of AKT. By inhibiting AKT serine-threonine kinase activity, ipatasertib may inhibit tumor growth and proliferation through mTOR, as well as activate apoptotic signaling.1,6

Image: Ipatasertib and Akt

 

3 Preclinical data have shown that ipatasertib induced tumor growth delay or regression in AKT-activated tumor cells and xenograft models.1 Ipatasertib continues to be investigated in ongoing clinical studies.

Inhibitory effect of ipatasertib on the PI3K/AKT signaling pathway

FOXO=Forkhead box O; GSK3=glycogen synthase kinase 3; mTORC=mammalian target of rapamycin complex; PDK1=phosphoinositide-dependent kinase-1; PI4,5P2=phosphatidylinositol 4,5-bisphosphate; PIP3=phosphatidylinositol 3,4,5-trisphosphate; RTK=receptor tyrosine kinase.

References

  1. Lin J, Sampath D, Nannini MA, et al. Clin Cancer Res. 2013;19:1760-1772. PMID: 23287563
  2. Slomovitz BM, Coleman RL. Clin Cancer Res. 2012;18:5856-5864. PMID: 23082003
  3. Huang WC, Hung MC. J Formos Med Assoc. 2009;108:180-194. PMID: 19293033
  4. Beeram M, Tan QT, Tekmal RR, Russell D, Middleton A, DeGraffenried LA. Ann Oncol. 2007;18:1323-1328. PMID: 17693645
  5. Nitulescu GM, Margina D, Juzenas P, et al. Int J Oncol. 2016;48:869-885. PMID: 26698230 
  6. Hung CM, Garcia-Haro L, Sparks CA, Guertin DA. Cold Spring Harb Perspect Biol. 2012;4:1-17. PMID: 23124837