DIACC2010 / DIACC2020, KIF20A inhibitor

A selective KIF20A inhibitor to tackle highly proliferative cancers

By combining the great efficacy and broad therapeutic scope of chemotherapy and the safety potential of targeted therapy, the KIF20A inhibitor DIACC2010 brings chemotherapy in the era of precision medicine. The preclinical proof-of-concept recently established in acute myeloid leukemia, supports the regulatory preclinical development of this sole-in-class drug candidate.

Paving the way for targeted chemotherapy

Uncontrolled cell proliferation is the “hallmark” of cancers. Thus, antimitotic agents[1] (such as taxanes or vinca alkaloids that hinder the dynamic of microtubules, the intracellular engine that controls cell division and shape) have been successfully used for decade in the treatment of solid and blood cancers[2][3] but they remain highly toxicity, calling for the development of alternatives approaches to block cell division.
Targeting kinesins has emerged as one such alternative. This family of motor proteins convert the energy stored in ATP into mechanical work[4]. Involved in cell division, some of them (KSP or CENPE) have been subject to the development of inhibitors, but these efforts have thus far remained unfruitful due to low efficacy of the resulting drugs. Given its unique profile and data from in vitro and in vivo studies, DIACC2010 could change the game, paving the way for targeted chemotherapy.

The KIF20A kinesin acts on cell division and intracellular trafficking

The microtubule associated motor protein KIF20A (previously called MKLP2) plays a key role in cell division[5] but also within the Golgi apparatus[6] (the cell’s “traffic center”) where it drives is responsible for forming and initiating the transport of secretion vesicles to the cell surface[7][8], a mechanism that is essential to ensure the secretion of molecules that promote the growth and migration of cancer cells. Thus, in the absence of KIF20A, the growth of pancreatic cancer cells is significantly inhibited[9].

KIF20A is overexpressed in many cancers[10][11][12][13][14][15] and this dysregulation is associated with disease progression and poor survival outcome[16][17]. Thus, unlike chemotherapies, KIF20A inhibition should specifically affect cancer cells and spare healthy cells.

The KIF20A inhibitor DIACC2010: a sole-in-class drug candidate with highly potent and selective cytotoxic and cytostatic powers

Originally identified[18] in partnership with the discoverers of anti-tubulin agents docetaxel and vinorelbine (ICSN, CNRS, Paris Saclay University), DIACC2010 is a small molecule that specifically inhibits KIF20A, while preserving the activity of other related kinesins. After turning KIF20A off:

  • Secretion from the Golgi apparatus is blocked, preventing the release of newly synthezised proteins, essential for cancer progression and metastasis. Furthermore, Golgi body progressively fragments, which leads to cancer cell death.

  • Cytokinesis, the last step of mitosis (when the two daughter cells become physically separated) is also blocked. Inhibition of KIF20A leads to multinucleated cells and mitotic arrest.

Figure 1: the dual mode of action of DIACC2010

Figure 1

E-Poster presented at AACR2022

Video file

Preclinical results

DIACC2010 exhibits high in vitro cytotoxic activity against a very large number of human cancer cell lines, including Acute Myeloid Leukemia (AML) cell lines. In AML, DIACC2010 is also active against cell lines resistant to the reference chemotherapy, cytarabine. In vivo, DIACC2010 significantly increases the survival of mice implanted with an AML cell line (MOLM-14), in a dose-dependent manner.  All these preclinical data demonstrate that DIACC2010 has a very high efficacy profile in AML, which strongly supports its regulatory and clinical development in this indication[19][20].

Preliminary preclinical studies also indicate that DIACC2010 has a promising efficacy profile in solid tumors, especially in pancreatic cancer. Improving the efficacy of DIACC2010 could be achieved through an increased bioavailability. This is one of the objectives of the DIACC2020 program.


KIF20A inhibitor as novel payload class for ADCs

Antibody–drug conjugates (ADCs) are becoming increasingly prominent in the oncology landscape. Thirteen ADCs[1][2] are marketed worldwide in solid and blood cancers and more than 100 drug candidates[3] are currently being evaluated in clinical trials. While linker and conjugation technologies have meaningfully improved over time only 6 payloads are used at commercial stage. New payload generation development is the next key success factor in this area.

The KIF20A inhibitor is a potent, selective and and safe molecule that fits ideally as a new payload candidate. Through the DIACC2020 program, the company intends to validate its potential in the field. In the medium term, these developments will lead to partnerships with specialized companies.

Preclinical Development

After having successfully completed the feasibility of conjugation and drug release with a traditional peptidic cleavable linker, the company has filed a first patent in mid-2022. Assessment of preclinical efficacy of antibody DIACC2010 conjugate is currently evaluated in acute myeloid leukemia and solid tumors is ongoing, aiming to demonstrate superior efficacy and improved therapeutic index, as compared to marketed ADCs.