Developers of carfilzomib take another shot at multiple myeloma

A FierceBiotech’s report[1] listed Cleave Biosciences as one of the most noteworthy private biotech upstarts. This small biotech company was co-founded by Raymond Deshaies and Larry Lasky. Prior to Cleave, they co-founded Proteolix in 2003 and successfully developed a proteasome inhibitor called carfilzomib.

Cleave’s lead candidate, CB-5083, is a first-in-class inhibitor of p97 which delivers the ubiquitinated protein to the proteasome. Genetic knockdown of p97 leads to cell death in a number of cancer cell lines. P97 inhibitors target the upstream of proteasome, which may provide greater efficacy.

Raymond Deshaies’ laboratory identified a hit called DBeQ[2] in a high-throughput screen. Later, they synthesized more than 500 p97 inhibitors[3] and finally selected CB-5083 as a drug candidate. Genentech and Myriad Pharmaceuticals have also reported potent p97 inhibitors[4,5].

CB-5083 demonstrated anti-tumor activity in lung cancer (A549), colon cancer (HCT116), and multiple myeloma (RPMI8226) xenograft models at dose of 50-150 mg/kg. Notably, CB-5083 demonstrated activity in solid tumors. Cleave has initiated phase I clinical trial in patients with multiple myeloma in September 2014. Phase I study for solid tumors will begin in the 4th quarter of 2014.

Cleave has raised $52 million in Series A financing. It all looks promising.

[1] FierceBiotech’s 2014 Fierce 15

http://www.fiercebiotech.com/special-reports/fiercebiotechs-2014-fierce-15

[2] Proc Natl Acad Sci USA. 2011, 108(12), 4834-4839.

[3] ChemMedChem. 2013, 8(2), 297-312.

[4] Nat Chem Biol. 2013, 9(9), 548-556.

[5] Bioorg Med Chem Lett. 2010, 20(5), 1677-1679.

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