DIACC2010 / DIACC2020, KIF20A inhibitor

A KIF20A inhibitor to disrupt cell division and intracellular transport in highly proliferative cancers

Chronic cell proliferation is an intrinsic characteristic of all cancers and developing therapies that block the mechanisms responsible for cell division, or mitosis, has been a common goal in cancer research over several decades. A number of tubulin inhibitors, such as taxanes or vinca alkaloids, have been developed and are commonly used as cancer chemotherapeutics to block mitosis, but they are associated with high toxicity to healthy tissue, calling for the development of alternatives to block cell division. Targeting kinesins has emerged as one such alternative. Kinesins are a family of motor proteins that utilizes the energy released from ATP hydrolysis to move unidirectionally along microtubules inside the cell [1] to accomplish different functions. Some kinesins, like KSP (also known as Eg5) or CENPE, are involved in the progression through mitosis and have therefore been subject to the development of inhibitors, but these efforts have thus far remained unfruitful due to low efficacy of the resulting drugs.

DIACC2010 is a “sole-in-class” KIF20A inhibitor that disrupts the Golgi apparatus (the tumor’s “traffic center”) and cell division. By combining the great efficacy and broad therapeutic scope of chemotherapy and the safety of targeted therapy, DIACC2010 brings chemotherapy into the era of precision medicine. The drug candidate should enter clinical trials in 2022.

The KIF20A kinesin acts both in cell division and secretion

KIF20A is a kinesin also known as RAB6KIFL or MKlp2. The protein, which belongs to the Kinesin 6 family, is overexpressed in a wide range of malignant tumors [2, 3, 4, 5, 6, 7] and this overexpression is often associated with poor prognosis [8, 9]. KIF20A is required during mitosis, where it is responsible for the relocation of a series of proteins to the equator of the dividing cell to allow for the physical separation of the cytoplasm of the two nascent daughter cells, a process known as cytokinesis [10, 11].
In addition to its role in mitosis and unlike previously targeted mitotic kinesins, KIF20A is also essential at the Golgi apparatus, where it was initially found to localize[12]. The Golgi is an organelle that ensures protein packaging into vesicles for delivery to targeted destinations. In particular, it is responsible for forming and initiating the transport of secretion vesicles to the cell membrane, a mechanism that is essential to ensure the secretion of growth and other factors that promote the proliferation and migration of malignant cells [13]. Within the Golgi apparatus, kinesin KIF20A plays at least two major roles: it regulates intra-organelle transport and is critical for the formation of secretion vesicles; research by Miserey-Lenkei and colleagues has demonstrated that this kinesin is required for secretion vesicles to detach from the Golgi apparatus and to initiate their transport to the cell membrane via microtubules [14].

A potent small molecule to inhibit KIF20A functions

DIACCURATE has developed the very first small molecule that targets KIF20A and which was identified in collaboration with the chemistry center ICSN, discoverers of anti-tubulin agents docetaxel and vinorelbine [15] .
This new chemotherapy candidate specifically inhibits the ATPase activity of KIF20A while preserving the activity of other related kinesins, and thereby blocks two pathways of great importance to cancer cell survival and proliferation (figure 1):

  1. First, as expected from KIF20A’s role during mitosis, exposure of tumor cells to DIACC2010 causes cytokinesis and mitosis to fail, leading to the accumulation of undivided cells with more than one nucleus and inhibiting cell growth. By blocking mitosis, DIACC2010 acts as a cytostatic agent, preventing cells from completing cell division, but not directly causing their death.
  2. Second, DIACC2010 inhibits KIF20A at the Golgi apparatus and acts as a cytotoxic agent that leads to fragmentation of the organelle, which is predictive of cell death by apoptosis [16].

Importantly, in vivo preclinical data indicates that DIACC2010 improves survival in mouse models of acute myeloid leukemia (AML) and reduces tumor growth in pancreatic cancer models. Lastly, while a potent anti-mitotic, this inhibitor is not expected to cause toxicity in healthy tissues as do anti-tubulin agents, and in fact no clinically significant toxicities have been observed with inhibitors of other mitotic kinesins [17], arguing towards a favorable toxicity profile for DIACC2010.

Figure 1: the dual mode of action of DIACC2010

DIACC2010 MOA

 

Development plan and first targeted indications

Diaccurate is currently conducting CMC development and preclinical regulatory studies to perform clinical studies for DIACC2010 in high mitotic index cancers such as hematologic malignancies and expects to initiate a first clinical trial in AML by 2022.

For solid tumors, Diaccurate has undertaken two complementary strategies to increase drug delivery at the tumor site (DIACC2020 program):

  • The generation of albumin-binding prodrugs (in vivo), to increase its circulating half-life and promote intracellular delivery.
  • The generation of Antibody-Drug Conjugates, where antibodies that specifically target tumor antigens will be loaded with DIACC2010 to extend the therapeutic window.

While studies for technological proof-of concept of these two strategies are under way, proof of concept in animal models is expected to start mid-2022.

References

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  11. Adriaans IE, et al. MKLP2 Is a Motile Kinesin that Transports the Chromosomal Passenger Complex during Anaphase. Curr Biol. 2020
  12. Echard A, et al. Interaction of a Golgi-associated kinesin-like protein with Rab6. Science. 1998
  13. da Cunha BR, et al. Cellular Interactions in the Tumor Microenvironment: The Role of Secretome. J Cancer. 2019
  14. Miserey-Lenkei S, et al. Coupling fission and exit of RAB6 vesicles at Golgi hotspots through kinesin-myosin interactions. Nat Commun. 2017
  15. Tcherniuk S, et al. Relocation of Aurora B and survivin from centromeres to the central spindle impaired by a kinesin-specific MKLP-2 inhibitor. Angew Chem Int Ed Engl. 2010
  16. Mukherjee S, et al. Fragmentation of the Golgi apparatus: an early apoptotic event independent of the cytoskeleton. Traffic. 2007
  17. Jackson JR , et al. Targeted anti-mitotic therapies: can we improve on tubulin agents? Nat Rev Cancer. 2007