DIACC2010 / DIACC2020, KIF20A inhibitor

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

Uncontrolled cell proliferation is the “hallmark” of cancers.
Microtubules are long hollow tubes made of assembled tubulin molecules. In perpetual agitation (they continuously assemble and disassemble their tubulin monomers), they are involved in many phenomena, especially in cell division. They form a very controlled structure, called the mitotic spindle, which captures, aligns and distributes the chromosomes equally between the two daughter cells. Defects in the formation of this spindle can cause the division process to stop. By interfering with the dynamics of microtubules, tubulin inhibitors such as taxanes or vinca alkaloids disrupt the mitotic spindle [1], thus halting mitosis and cell proliferation. For many years, these chemotherapies (more commonly known as spindle poisons) have been successfully used in the treatment of many solid and hematological cancers [2,3].

The KIF20A kinesin acts both in cell division and secretion

KIF20A is a kinesin also known as RB6K or MKlp2. The protein, which belongs to the Kinesin 6 family. Its expression varies throughout the cell cycle and is maximal during mitosis [4], in which it plays a key role. KIF20A is overexpressed in a wide range of malignant tumors (cancer of the lungs, liver, stomach, pancreas, ovaries, cervix…),  [5,6,7,8,9,10] and this overexpression is often associated with poor prognosis [11,12].  Thus, unlike chemotherapies, DIACC2010's action should specifically affect cancer cells and spare healthy cells. Unlike mitotic kinesins like KSP or CENPE, the function of KIF20A is not limited to cell division. KIF20A is also essential at the Golgi apparatus, where it was initially found to localize [13]. The Golgi is an organelle that ensures protein packaging into vesicles for delivery to targeted destinations. 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  [14]. In the absence of KIF20A, the growth of pancreatic cancer cells is significantly inhibited  [15].

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. At the Curie institute, Bruno Goud and his team, in collaboration with Diaccurate, 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  [16]. Because of the central role played by KIF20A in the Golgi apparatus, its inhibition is expected to severely compromise the functions of this organelle, whose fragmentation is associated with cell death by apoptosis [17].

A potent small molecule to inhibit KIF20A functions FRFR

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 [18].
Once inside the cancer cell (their cell membrane is permeable to kinesin), DIACC2010 specifically inhibits the motor activity of KIF20A, while preserving the activity of other related kinesins. In the absence of KIF20A (figure 1):

  • Secretion from the Golgi apparatus is blocked, preventing the release of proteins and growth factors, essential for its development, into the tumor microenvironment. The Golgi apparatus progressively fragments, which leads to cancer cell death. DIACC2010 acts here as a cytotoxic agent.
  • The cancer cell is unable to initiate cytokinesis, which blocks cell division. DIACC2010 acts as a cytostatic agent. It prevents cells from completing mitosis but does not directly cause their death.

Figure 1: the dual mode of action of DIACC2010

Figure 1

E-Poster presented at AACR2022

Video file

Preclinical results

  • Acute Myeloid Leukemia (AML) : DIACC2010 exhibits high in vitro cytotoxic activity against a very large number of human AML cell lines, including those resistant to the reference chemotherapy, cytarabine.  DIACC2010 significantly extends the survival of mice implanted with an AML cell line (MOLM-14), with a dose-dependent efficacy.  All these preclinical data demonstrate that DIACC2010 has a very high efficacy profile in AML, which justifies its regulatory and clinical development in this indication. 
  • Pancreatic Cancer : DIACC2010 exhibits high in vitro cytotoxic activity against a large number of human pancreatic cancer lines, with a level of efficacy close to the reference chemotherapy, gemcitabine. 
    DIACC2010 significantly inhibits tumor growth in mice implanted with pancreatic cancer cells (PANC02). In this model, sensitive to the reference chemotherapy, gemcitabine, DIACC2010 has the same efficacy as an anti-PDL1 antibody treatment. 

Preliminary preclinical studies 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 the objective of the DIACC2020 program.
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Development plan and first targeted indications

The clinical development of DIACC2010 aims to establish its safety and efficacy profile in different subgroups of AML patients in a Phase I/II dose escalation and cohort extension study.

As a priority, DIACC2010 will be evaluated in relapsed or refractory patients, i.e. in the subgroups with the highest medical need:

  • The first part of the Phase 1 dose-escalation study will aim to determine the safety profile of DIACC2010 as a single agent, to determine the recommended dose for future phases and to evaluate early signals of clinical activity.
  • The second part of the study will consist of parallel cohorts, in 2 more targeted relapsed patient populations, which will evaluate DIACC2010 in combination:

○ With cytarabine in young or fit patients, justifying the use of aggressive chemotherapy (cohort A);
○ With azacitidine (Vidaza® from BMS) in patients who are older or too fragile to be eligible for aggressive chemotherapy (cohort B);

  • In the light of the clinical results in relapsed AML, DIACC2010 will also be evaluated in triple combination with azacitidine + venetoclax (Venclyto® from Abbvie), in elderly and/or fragile patients who are not eligible for stem cell transplantation and who are naïve to any treatment.

Through the DIACC2020 program, the Company intends to explore the potential of DIACC2010 in solid tumors by increasing its bioavailability. These developments will lead to partnerships with specialized companies.

References

  1. Marty et al. Taxoids: a new class of cytotoxic agents. Nouv Rev Fr Hematol. 1994;36 Suppl 1:S25-8. 
  2. Dumontet et al. Microtubule-binding agents: a dynamic field of cancer therapeutics [published correction appears in Nat Rev Drug Discov. 2010 Nov;9(11):897]. Nat Rev Drug Discov. 2010;9(10):790-803. 
  3. Jackson et al. Targeted anti-mitotic therapies: can we improve on tubulin agents? Nat Rev Cancer. 2007 Feb;7(2):107-17. 
  4. Hill et al. The Rab6-binding kinesin, Rab6-KIFL, is required for cytokinesis. EMBO J. 2000 Nov 1;19(21):5711-9. 
  5. Kikuchi et al. Expression profiles of non-small cell lung cancers on cDNA microarrays: identification of genes for prediction of lymph-node metastasis and sensitivity to anti-cancer drugs. Oncogene. 2003 Apr 10;22(14):2192-205. 
  6. Zhao et al. Overexpression of KIF20A confers malignant phenotype of lung adenocarcinoma by promoting cell proliferation and inhibiting apoptosis. Cancer Med. 2018 Sep;7(9):4678-4689.
  7. Groth-Pedersen et al. Identification of cytoskeleton-associated proteins essential for lysosomal stability and survival of human cancer cells. PLoS One. 2012;7(10):e45381. 
  8. Yan et al. Genistein-induced mitotic arrest of gastric cancer cells by downregulating KIF20A, a proteomics study. Proteomics. 2012 Aug;12(14):2391-9. 
  9. Gasnereau et al. KIF20A mRNA and its product MKlp2 are increased during hepatocyte proliferation and hepatocarcinogenesis. Am J Pathol. 2012 Jan;180(1):131-40. 
  10. Imai et al. Identification of HLA-A2-restricted CTL epitopes of a novel tumour-associated antigen, KIF20A, overexpressed in pancreatic cancer. Br J Cancer. 2011 Jan 18;104(2):300-7. 
  11. Sheng et al. Upregulation of KIF20A correlates with poor prognosis in gastric cancer. Cancer Manag Res. 2018 Nov 23;10:6205-6216. 
  12. Shen et al. KIF20A Affects the Prognosis of Bladder Cancer by Promoting the Proliferation and Metastasis of Bladder Cancer Cells. Dis Markers. 2019 Apr 9;2019:4863182. 
  13. Goud et al. Interaction of a Golgi-associated kinesin-like protein with Rab6. Science. 1998 Jan 23;279(5350):580-5. 
  14. da Cunha et al. Cellular Interactions in the Tumor Microenvironment: The Role of Secretome. J Cancer. 2019 Aug 7;10(19):4574-4587. 
  15. Taniuchi et al. Down-regulation of RAB6KIFL/KIF20A, a kinesin involved with membrane trafficking of discs large homologue 5, can attenuate growth of pancreatic cancer cell. Cancer Res. 2005 Jan 1;65(1):105-12. 
  16. Goud et al. Coupling fission and exit of RAB6 vesicles at Golgi hotspots through kinesin-myosin interactions. Nat Commun. 2017 Nov 1;8(1):1254. 
  17. Mukherjee et al. Fragmentation of the Golgi apparatus: an early apoptotic event independent of the cytoskeleton. Traffic. 2007 Apr;8(4):369-78. 
  18. Tcherniuk 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 Oct 25;49(44):8228-31.