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Novel Isoprenylcysteine Carboxyl Methyltransferase (ICMT) Inhibitors That Suppress K-RAS Driven Cancer


THE CHALLENGE

Pancreatic cancer is a leading cause of cancer mortality – its estimated 5-year survival rate is less than 5%. About 90% of pancreatic cancers are pancreatic ductal adenocarcinoma (PDAC), which is mostly fatal. Surgery is currently the lone curative option but as most patients are diagnosed at late stage, less than 20% of patients are eligible for surgery. Aside from surgery, there has been no major advancements in the treatment of PDAC.


THE SOLUTION

The Ras family is a protein family of GTPases implicated in oncogenesis and tumour progression. Activating mutations in Ras have been found in almost 30% of all cancers, particularly in up to 90% of pancreatic cancers. These data suggest that inhibitors of Mnk1 and Mnk2 may be effective anticancer drugs and are likely to have minimal side effects.

 


Figure 1: Post Translational Modification of Ras Proteins. In the first step of the modification, a 15-carbon farnesyl or a 20-carbon geranylgeranyl lipid is covalently attached to the Cysteine residue of the CaaX motif. The second step involves the cleaving of the three amino acids (i.e., the -aaX) by RceI (Ras converting enzyme 1) protease. In the last step of the modification the newly exposed isoprenylated cysteine residue is methylated by ICMT. The post translational modification increases the hydrophobicity of the signalling molecules and directs it to the membrane. Drugs Fut 2006, 31(5): 437.

Isoprenylcysteine carboxyl methyltransferase (ICMT) is a eukaryote specific integral membrane enzyme. It is involved in the final step of the post translational modification of Ras proteins, which is crucial for their proper cellular function. We aim to discover ICMT inhibitors with therapeutic activity in cancers driven by oncogenic Ras family members.

THE ADVANTAGE

There is growing evidence that points to the importance of ICMT-catalysed modification of Ras proteins in oncogenesis. We have validated the ICMT target in-vivo, the knock-out of ICMT abolished tumor growth of MiaPaCa2 (pancreatic cancer cell line) cells in mice. Similar results were also obtained by targeting ICMT with shRNA.

Figure 2: Loss of ICMT function obliterates the ability of MiaPaCa-2 cancer cell line carrying oncogenic mutant RAS to form tumors in vivo. (a) Growth of ICMT-wild-type MiaPaCa-2 xenografts. (b) Measured sizes of ICMT-null MiaPaCa-2 implants from ICMT-null, 3 × 106 cells were implanted for each MiaPaCa-2 xenograft, both ICMT wild-type and ICMT-null. (c) The mean final tumor size at the last measured time point for both ICMT wild-type and ICMT-null MiaPaCa-2 xenografts. (d) Image of a representative mouse showing the tumors at the time of killing. Red arrow: MiaPaCa-2-ICMT-wild-type tumor; blue arrow: remnant of the MiaPaCa-2-ICMT-null injection. Oncogene (2017) 36, 3934–3942.

The use of ICMT inhibitors may also be a better approach as it overcomes the association of Ras proteins with the plasma membrane. This could prove to be a more effective strategy to suppress K-ras driven oncogenesis.

CURRENT STATE OF DEVELOPMENT

We have established an ICMT biochemical assay amenable to high throughput  screening. It resulted in the identification of multiple hit scaffolds. The hit to lead studies further provided a good SAR. The validation of compound binding to the target was demonstrated using structural studies (NMR).

THE OPPORTUNITY

We are seeking co-discovery partners to advance this program. Specifically, to carry out lead optimization studies and to conduct animal efficacy studies.

 

CONTACT @ EXPERIMENTAL THERAPEUTICS CENTRE

Mr Marvin Ng, Email: mng@etc.a-star.edu.sg
Ms Tam Lay Hong, Email: lhtam@etc.a-star.edu.sg

31 Biopolis Way, #03-01
Nanos, Singapore 138669
T: +65 6478 8767

www.a-star.edu.sg/etc