GADD45β/MKK7 inhibitor DTP3 sounds promising in multiple myeloma

Here is a paper[1] published in the journal Cancer Cell on October 13. Scientists at Imperial College London have developed a first-in-class drug called DTP3 and plan to test it in multiple myeloma patients next year.

DTP3 is a D-tetrapeptide, which disrupts the GADD45β/MKK7 complex, selectively kills multiple myeloma cells in vitro and significantly prolongs the survival of mice at a dose of 29 mg/kg (mOS: 26 days vs 161+days), without producing any apparent side effect.

GADD45β is an anti-apoptotic factor upregulated by the activation of NF-κB[2]. The binding of GADD45β to MKK7 suppresses the JNK apoptotic cascade. Thus, the GADD45β/MKK7 interaction is a crucial molecular link between the NF-κB and JNK pathways.

The NF-κB signaling pathway has been found for many years. However, no specific NF-κB or IKKβ inhibitor has been approved. Global suppression of NF-κB may unavoidably cause side effects because this protein is found in almost all cell types.

The authors took a different approach. They put their eyes to the downstream of NF-κB. Finally, they found GADD45β which is responsible for cancer specifically.

Professor Guido Franzoso, who led the research, has thrown himself into this field over ten years. They had previously identified GADD45β as a potent inhibitor of apoptosis. Later, they found that GADD45β is highly expressed in multiple myeloma cells and assoc iates with aggressive disease.

Franzoso’s group screened a combinatorial library of 20,736 L-tetrapeptides and found two that disrupted the GADD45β/MKK7 complex. Further optimization led to DTP3 which binds to endogenous MKK7 without any off-target effect in a panel of 142 human kinases.

The current treatment for multiple myeloma includes chemotherapy and steroids combined with proteasome inhibitors and immunomodulatory agents. The FDA has granted Breakthrough Therapy Designation to elotuzumab (anti-SLAMF7) developed by Bristol-Myers Squibb and AbbVie in May 2014.

GADD45β/MKK7 inhibitors and Cleave Biosciences’ p97 inhibitors may provide more options for patients with multiple myeloma. A small company called Kesios Therapeutics has been founded to develop DTP3 and other candidates based on Franzoso’s research.

[1] Cancer Cell. 2014, 26(4), 495-508.

[2] Nature. 2001, 414(6861), 308-313.

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