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COTI-2 is a novel small molecule that acts by inhibiting Akt/PKB (Protein kinase B) phosphorylation that leads to caspase-9 activation in cancer cells resulting in tumor cell death. COTI-2 has demonstrated greater selectivity as well as an improved safety profile and pharmacokinetics in comparison to other Akt inhibitors. COTI-2 is easily synthesized and has good in vitro and in vivo efficacy against multiple human cancers including small cell lung, non-small cell lung, colon, brain, ovarian, endometrial, triple negative breast and pancreatic. COTI-2 test results show it to be highly effective as a single agent therapy and as a combination therapy in a number of animal models of human cancers.

How does COTI-2 work?
• COTI-2 promotes tumor cell death by interfering with Akt2 in the
   PI3K/Akt/mTOR pathway.
• Experimental evidence indicates that COTI-2 prevents the activation of Akt2,
   thereby preventing its cancer promoting activities.
• Human cancer cells exposed to COTI-2 exhibit reduced levels of activated
   Akt2 compared to untreated cells.
• COTI-2 did not exhibit any activity towards cells in which Akt2 activity was
   removed by silencing RNA. Therefore, in the absence of its target (Akt2)
   COTI-2 was unable to promote death in cancer cells. This indicates that
   Akt2 is the specific target of COTI-2.

Current Status of the COTI-2 Development Program
• Experimental evidence indicates that COTI-2 is highly effective against
   several human cancer cell lines.
• COTI-2 is also highly effective against human colon cancer cell lines with
   abnormal/mutated KRAS, which are otherwise not sensitive to Erbitux®.
• COTI-2 has demonstrated a good in vitro and in vivo pharmacokinetic profile.
• COTI-2 has demonstrated low toxicity in vitro and in vivo.
• COTI-2 is highly effective as a single agent in multiple animal models of
   human cancers, including SCLC, colon, brain, ovarian, pancreatic cancer and
• COTI-2 is highly effective as a combination agent in multiple animal
   models of human cancers, including endometrial, ovarian, and
   pancreatic cancer.

How does COTI-2 differ from other cancer treatments?
• Treatment by conventional cancer chemotherapy involves the killing of all
   growing and dividing cells (cancer or otherwise) in the body. This often
   leads to significant toxic side effects in patients.
• Unlike conventional chemotherapy, COTI-2 specifically targets and destroys
   tumor cells.
• COTI-2 targets tumor cells with abnormally high levels of active Akt2.
• COTI-2 has demonstrated very low toxicity in normal human cells compared
   to human cancer cells.
• COTI-2 has demonstrated very low toxicity in rodents.
• Many studies have shown that the activation of Akt2 causes tumor cells to
   become resistant to chemotherapeutic drugs and signal molecule inhibitors.
   (e.g., Gleevec®, Iressa®,and Herceptin®).
   Unlike the conventional therapeutic agents paclitaxel and cisplatin, COTI-2
   did not induce resistance in cancer cells.  COTI-2 was actually highly effective
   against paclitaxel and cisplatin resistant cancer cells.
• The combined scientific evidence indicates that COTI-2 is an ideal agent for
   combination therapy with current standard agents.

Projected Developmental Activities for the next 12 months
• The development of an optimal oral formulation for COTI-2 that can be used
   for Investigational New Drug (IND) enabling experiments and Phase 1.
• An IND enabling 28 day/acute toxicity study using the optimally formulated
   COTI-2 in two species.
• Complete the balance of FDA enabling research for the first-in-man
   multicentre United States based Phase 1 Clinical Trial.

To request a non-confidential data package please contact Wayne Danter, President and CEO.

COTI-2 Fact Sheet

Recent COTI-2 Press Releases

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