Cryptophycin analog

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The cryptophycins are a group of cyanobacterial depsipeptides with a remarkable biological activity against multi-drug-resistant (MDR) cancer cells. As a potent class of cytotoxic agents the were evaluated as a payload for antibody drug conjugate payloads.

In various studies, free cryptophycin analog 1 has displayed cell activity in an order of magnitude more potent than payloads in approved antibody-drug conjugates, including Monomethyl Auristatine E or MMAE and DM1.[1]

This potency increase was also reflected in the activity of the antibody-drug conjugate attached via a either cleavable or non-cleavable linker to cryptophycin. [1]

Mechanism of Action
Cryptophycins deplete microtubules through interaction with tubulin, thereby preventing cell division. They are capable of inducing apoptosis, possibly through other mechanisms in addition to that mediated by microtubule inhibition.

Cryptophycins were originally obtained from cyanobacteria. A synthetic analogue, known as cryptohycin-52 (LY355703), a novel antitubulin drug with in vitro and in vivo activity in non-small cell lung cancer has been investigated in clinical trials. Following promising phase I data, a multicenter phase II trial demonstrated disease stabilization in 40% of patients with platinum-resistant advanced ovarian cancer and non-small cell lung cancer (NSCLC). However, the development of the trial drug was discontinued because of lack of responses in patients with advanced NSCLC in spite of significant neurological toxicity. [2][3]

Toxicity

One of the major limitations in the use of microtubule-targeted agents, including cryptophycin, is the high rate of peripheral neurotoxicity, a major potentially dose-limiting side effect induced by these compounds. [4] Researchers have found that peripheral neuropathy is a limiting factor in the development of cryptophycin, leading to termination of the (pre-) clinical development of this agent.

While cryptophycin was considered extremely toxic and unacceptable to be used as chemotherapeutic drugs, new developments, including antibody-drug conjugates, have ‘resurrected’ the the potential use of this agent.


Last Editorial Review: January 11, 2016

Image: Cryptophycin analog.  Courtesy: © Sunvalley Communication, LLC. Used with permission.