DZ-2384

DZ-2384 is a novel microtubule targeting agent (MTA) currently in preclinical development at Diazon Pharmaceuticals. The compound is being investigated for the treatment of potentially multiple different cancers as it exhibits potent anti-tumor activity across multiple preclinical models and has a unique mechanism of action that translates into a superior safety profile.

DZ-2384 targets a validated pathway in oncology

MTAs, primarily taxanes and vinca alkaloids, are a validated class of anti-cancer drugs and are among the most extensively used chemotherapies in oncology. Currently, they are deployed in the standard of care for over 15 cancer indications.

However, durable responses are often restricted by dose-limiting lack of efficacy and associated toxicities at therapeutic doses, resulting in dose reductions or discontinuation of treatment altogether. This is particularly true for attendant neuropathies, which can be severe and can even persist long after the cessation of treatment. Toxicities associated with the current drugs in this class can also limit their optimal use in combination with other treatments, such as targeted agents, including immunotherapies. DZ-2384 is a highly potent new MTA. Based on extensive preclinical studies and its novel mechanism of action, Diazon believes that it can overcome these clinical liabilities. If so, DZ-2384 has the potential to capture a wide segment in the oncology market.

Diazonamide A

DZ-2384 is a refined, scalable synthetic derivative of a natural product, diazonamide A (DZA), produced by the marine sponge Diazona angulata1,2.

The motivation to develop DZ-2384 as an optimized DZA analog resulted from research conducted at the University of Texas Southwestern showing that early analogs of DZA exhibited potent anti-tumor activities in animal models, but with minimal overt toxicities3. The mechanism of action of DZA analogs, however, was unknown.

Distinct mechanism of action compared to other MTAs

Based on pharmacologic studies performed for Diazon and in the Laboratory for Therapeutic Development (LTD) at the Rosalind and Morris Goodman Cancer Research Centre of McGill University, Diazon selected DZ-2384 as a proprietary lead drug candidate for development in oncology.

A comprehensive study based on functional genomics, X-ray crystallography of drug-target complexes, and extensive biochemistry and cellular analyses of DZ-2384 has revealed a detailed molecular explanation for the novel mechanism of action of this compound4.

DZ-2384 exhibits a unique binding mode at the vinca site of tubulin, which imparts distinct effects on microtubule dynamics and structure that translate into potent anti-tumor efficacy and superior safety margins compared to other MTAs. Like other vincas, DZ-2384 inhibits the growth rate of microtubules; however, DZ-2384 also changes microtubule dynamics in a manner consistent with the preservation of the microtubule network in interphase cells and in primary cortical neurons. X-ray crystallography and electron microscopy studies showed that DZ-2384 causes a straightening of curved protofilaments, resulting in an enhanced rescue of depolymerizing microtubules in interphase cells. This is proposed to favor polymerized tubulin and may account for the preservation of cellular interphase microtubule dynamics and the superior safety for this class of compound. At mitosis, defects in the mitotic spindle caused by DZ-2384 are sufficient to trigger a potent induction of apoptosis, resulting in tumor cell lethality4.

DZ-2384 Schematic
Microtubules in normal and cancer cells are very dynamic. The tubulin dimers that makes up the microtubules continually undergo cycles of polymerization (growth) and de-polymerization (shrinkage). “Rescue” refers to the change from a shrinking to a growing microtubule and “catastrophe” is the change from growing to shrinking; pausing is when the microtubule is static and neither growing nor shrinking. Both DZ-2384 and vinca alkaloids (VINCAS) function by reducing the growth rate of tubulin to form microtubules. This inhibits the ability of cancer cells to divide. A unique feature of DZ-2384 is that it causes a straightening of the tubulin protofilament structure and stimulates the frequency of microtubule rescues helping to preserve the microtubule network in normal cells, but not rapidly dividing cells. In contrast VINCAS increase tubulin protofilament curvature leading to increased pause and catastrophe frequencies and a breakdown of the microtubule network in non-dividing cells, a phenomenon that can lead to neuronal cell damage and contribute to peripheral neuropathy.

Lack of neurotoxicity at effective doses

An important manifestation of the preservation of interphase microtubule dynamics in the presence of DZ-2384, including in neurons, is the absence of peripheral neuropathy in a rat model throughout the efficacious dose range4. As noted above, peripheral neuropathy can be a serious clinical liability for existing taxane- or vinca-based anti-mitotic drugs.

Highly efficacious in multiple tumor models

DZ-2384 exhibits potent anti-tumor activity both as a single agent and in combination in xenograft, patient-derived xenograft (PDX), and genetically engineered mouse (GEM) models of several oncologic indications4.

Based on our studies, as well as a high unmet medical need, Diazon plans to pursue phase 2 human proof-of-concept (PoC) trials, initially in metastatic triple negative breast cancer (mTNBC) followed by pancreatic ductal adenocarcinoma (PDA), measuring both drug efficacy and safety, including neuropathies, as end points.

1Li et al. Angewandte Chemie (2001) 40: 4770-3

2Ding et al. Angew Chem Int Ed Engl (2015) 54: 4818-22.

3Williams et al. Proc. Natl. Acad. Sci. USA (2007) 104:2074-9

4Wieczorek et al. Science Transl. Med. 2016 Nov 16;8(365):365ra159