ACTIVITY BY INHIBITING CDK8/19

BACKGROUND OF THE INVENTION

Field of the invention

The invention relates to the treatment of hematological malignancies. Summary of the related art

The deoxycytidine nucleoside analog Ι-β-arabinofuranosylcytosine (Cytarabine or AraC) is the principal chemotherapeutic agent used in the treatment of acute myeloid leukemia (AML). AraC is also used for other hematological malignancies, including acute lymphoblastic leukemia, chronic myelocytic leukemia, erythroleukemia, T-cell leukemia, acute monocytic leukemia, and mantle-cell lymphoma. AraC-containing chemotherapeutic regimens induce complete remission in 65-80% of newly diagnosed AML patients but a substantial minority of leukemias are intrinsically resistant to AraC. Furthermore, most of the initially responding patients relapse with resistant disease and poor response to subsequent therapies. As a result, the current overall survival rate for adult AML patients is less than 30% (Lamba, 2009; Momparler, 2013), and there is great need for improving the current AraC-containing regimens.

The mechanisms of resistance to AraC are varied and include inefficient cellular uptake of AraC due to low activity of its membrane transporter, hENTl, or increased expression of ABC transporters (drug efflux pumps), such as MRP7 and MRP8; reduced levels of AraC- activating enzymes, primarily deoxycytidine kinase (DCK); increased levels of inactivating enzymes, such as 5 ^' -nucleotidase (NT5C2) and cytidine deaminase (CD A), increased cellular dCTP pools that can compete with DNA incorporation of Ara-CTP, the active form of AraC (Lamba, 2009), and epigenetic changes that lead to resistance to AraC-induced apoptosis (Momparler, 2013).

Epigenetic changes in gene expression activating various mechanisms of drug resistance can be induced by treatment with chemotherapeutic drugs (Wilting and Dannenberg, 2012). This notion was originally proposed by one of the instant inventors, who demonstrated that exposure of leukemia cells to chemotherapeutic drugs, notably including AraC, leads to transcriptional activation of major drug resistance genes, such as those encoding ABC transporters MDR1 (Chaudhary and Roninson, 1993) and LRP (Komarov et al., 1998). Hence, inhibition of transcriptional reprogramming associated with drug resistance could potentially prevent the development of resistance to AraC.

CDK8 and CDK 19, two closely related (80% identity) transcription-regulating serine/threonine kinases, are alternative subunits of the regulatory CDK module of the Mediator complex that links transcription-initiating factors with RNA Polymerase II (Pol II) (Galbraith et al., 2010). CDK8/19 phosphorylate the C-terminal domain (CTD) of Pol II enabling the elongation of transcription (Donner et al., 2010; Galbraith et al., 2013). However, CDK8/19 are responsible for Pol II CTD phosphorylation specifically at the silent genes that become activated by transcription-inducing factors but they are not generally required for Pol II CTD

phosphorylation. As a result of this selective function, CDK8/19 inhibition has little effect on most cell types under homeostatic conditions (Porter et al., 2012) but it prevents transcriptional reprogramming triggered by various signals (Donner et al., 2010; Galbraith et al., 2013). In particular, CDK8/19 inhibitors potentiate the efficacy of DNA-dam aging chemotherapeutic agents by inhibiting chemotherapy-induced expression of anti-apoptotic factors (Porter et al., 2012). CDK8/19 has become an actively pursued target for drug discovery and development (Rzymski et al., 2015). Accordingly, CDK8/19 inhibitors have become well known in the art. Some of the published CDK8/19 inhibitors, aside from Senexin A (Porter et al., 2012) and Senexin B (US20140038958) include Cortistatin A (which, in addition to CDK8/19 also inhibits Rock kinases) (Cee et al., 2009), CCT251545 (Dale et al., 2015) and SEL120-34A (Rzymski et al., 2015).

Inhibitors of CDK8/19 strongly inhibit the proliferation of some but not all leukemia cell lines. (Pelish et al., 2015). The present inventors asked if CDK8/19 inhibition could be beneficial in the treatment of the majority of leukemias that do not respond to CDK8/19 inhibition alone. BRIEF SUMMARY OF THE INVENTION

The present inventors have surprisingly discovered that specific CDK8/19 inhibitors can be advantageously used for drastic improvement of leukemia treatment with AraC -containing chemotherapeutic regimens. Inhibition of CDK8/19 in combination with AraC treatment synergistically improves the effectiveness of either agent alone in the treatment of hematological malignancies by several orders of magnitude. This was found to be true for structurally unrelated specific CDK8/19 inhibitors and is a property of inhibition of CDK8/19, not just a specific inhibitor.

Thus, the present invention provides a method for enhancing the efficacy of AraC in the treatment of hematological malignancies, comprising inhibiting CDK8/19 in a hematological cancer cell in combination with contacting the cell with AraC. In some preferred embodiments, such inhibition of CDK8/19 in a hematological cancer cell is accomplished by contacting the cell with a small molecule compound that is a specific inhibitor of CDK8/19.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 A shows the effects of different concentrations of Senexin B and Cortistatin A on relative cell numbers in 16 leukemia cell lines.

Fig. IB shows the effects of different concentrations of Senexin B and Cortistatin A on the emergence of dead (Pi-positive) cells in 16 leukemia cell lines.

Figure 2 shows the growth-inhibitory effects of Senexin B, AraC, and their combination in HL60 leukemia cells upon 7 days of treatment.

Fig. 3 A shows cell growth, presented as fold change in the calculated total number of live (Pi-negative) cells, of HL60 leukemia cells untreated or treated with 50 nM AraC, 2,500 nM Senexin B, or a combination of 50 nM AraC + 2,500 nM Senexin B, for 20 days.

Fig. 3B shows the same results presented as fraction of surviving drug-treated cells relative to the control.

Fig. 3C shows changes in the percentage of dead (Pi-positive cells) during the course of treatment.

Fig. 4A shows the effects of 40-day treatment with 50 mM Ara C, 100 nM Cortistatin A, and combinations of AraC with Cortistatin A or different concentrations of Senexin B on HL60 cell growth. The first number indicates the concentration of AraC (nM) and the second number of Senexin B or Cortistatin A (nM).

Fig. 4B shows the effects of 50 nM AraC and 2 uM Senexin B on the growth of naive (solid lines) or AraC-selected (dashed lines) HL60 cells over 8 days.

Fig. 5A shows cell growth, presented as fraction of surviving drug-treated cells relative to the control, of THP-1 acute monocytic leukemia cells treated with 250 nM AraC and 2,000 nM Senexin B, individually or in combination, over 60 days.

Fig. 5B shows changes in the percentage of dead (Pi-positive cells) during the course of treatment in the same experiment.

Fig. 6A shows cell growth, presented as fraction of surviving drug-treated cells relative to the control, of U937 leukemia cells treated with 25 nM AraC and 1,000 nM Senexin B, individually or in combination, over 93 days. Fig. 6B shows changes in the percentage of dead (Pi-positive cells) during the course of treatment in the same experiment.

Fig. 7A shows cell growth, presented as fraction of surviving drug-treated cells relative to the control, of MV4: 11 AML cells treated with 50 nM AraC and 250 nM Senexin B, individually or in combination, over 60 days.

Fig. 7B shows changes in the percentage of dead (Pi-positive cells) during the course of treatment in the same experiment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention relates to the treatment of hematological malignancies. The present invention provides a method for enhancing the efficacy of AraC in the treatment of

hematological malignancies, comprising inhibiting CDK8/19 in a hematological cancer cell in combination with contacting the cell with AraC. In some preferred embodiments, such inhibition of CDK8/19 in a hematological cancer cell is accomplished by contacting the cell with a small molecule compound that is a specific inhibitor of CDK8/19. In preferred embodiments, the hematological cancer cell is in the body of a patient, particularly a human patient.

In some embodiments, the hematological malignancy to be treated is selected from the group consisting of acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic myelocytic leukemia, erythroleukemia, T-cell leukemia, acute monocytic leukemia and mantle- cell lymphoma.

For purposes of the invention, the terms "a small molecule compound that specifically inhibits CDK8/19", and the like, mean a small molecule compound that inhibits one or more of CDK8 and CDK19 to a greater extent than it inhibits certain other CDKs. In some embodiments, such compounds further inhibit CDK8/19 to a greater extent than CDK9. In preferred embodiments, such greater extent is at least 2-fold more than CDK9. A "small molecule compound" is a molecule having a formula weight of about 800 Daltons or less.

"In combination with" generally means administering a specific CDK8/19 inhibitor and AraC in the course of treating a patient. Such administration may be done in any order, including simultaneous administration, as well as temporally spaced order from a few seconds up to several days apart. Such combination treatment may also include more than a single administration of the specific CDK8/19 inhibitor and AraC. The administration of the specific CDK8/19 inhibitor and AraC may be by the same or different routes.

In the methods according to the invention, the specific CDK8/19 inhibitor may be incorporated into a pharmaceutical formulation. Such formulations comprise the CDK8/19 inhibitor, which may be in the form of a free acid, salt or prodrug, in a pharmaceutically acceptable diluent (including, without limitation, water), carrier, or excipient. Such formulations are well known in the art and are described, e.g., in Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990. The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" means a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue, or organism, and that does not interfere with the effectiveness or the biological activity of the specific CDK8/19 inhibitor(s). Thus, compositions according to the invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. As used herein, the term

"pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the specific CDK8/19 inhibitor and exhibit minimal or no undesired toxicological effects. Examples of such salts include, but are not limited to, salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedi sulfonic acid, methanesulfonic acid, p-toluenesulfonic acid and polygalacturonic acid. The specific CDK8/19 inhibitor can also be administered as pharmaceutically acceptable quaternary salt known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula --NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide,— O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate). The specific CDK8/19 inhibitor is included in the

pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated. A "therapeutically effective amount" is an amount sufficient to provide synergy with AraC in the treatment of a hematological malignancy. The effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art. The dose in each patient may be adjusted depending on the clinical response to the

administration of specific CDK8/19 inhibitor and AraC. Administration of the pharmaceutical formulations in the methods according to the invention may be by any medically accepted route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In certain preferred embodiments, compositions of the invention are administered parenterally, e.g., intravenously in a hospital setting. In certain other preferred embodiments, administration may preferably be by the oral route.

The following examples are intended to further illustrate certain preferred embodiments of the invention and are not intended to limit the scope of the invention.

Example 1

CDK8/19 inhibitors strongly inhibit the growth of a subset of leukemia cell lines.

We have tested the effects of Senexin B and Cortistatin A on 7-day growth of 16 cell lines representing different types of human leukemia. The analysis was done by plating cells in 24-well plates (the number of cells per well for each cell line was based on their doubling time) and adding the compounds at several different concentrations [Senexin B: 78.125, 156.25, 312.5, 625, 1250, 2500, 5000 nM and Cortistatin A: 0.25, 2.5, 25, 250, 2500 nM], in duplicates, on the day after plating. Cell growth and survival were analyzed after 7 days of treatment by flow cytometry, after incubating cells with 10 μg/mL of propidium iodide (PI) for 10 minutes. Cells with an intact membrane do not take up PI, and therefore ΡΙ-positive cells must have ruptured membranes and are scored as dead cells. The growth-inhibitory effect of the drug is measured by the decrease in the number of live (Pl-negative) cells relative to the control (vehicle [DMSO] -treated) samples, as measured by flow cytometry using a BD LSRII instrument with a high-throughput (96-well) sampler. The effects of Senexin B and Cortistatin A on relative cell numbers in 16 leukemia cell lines are shown in Figure 1A. The corresponding IC50 values, calculated using the IC50 Tool Kit (www.ic50.tk), are presented in Table 1.

Table 1. Inhibitory effects of Senexin B and Cortistatin A on a panel of leukemia cell lines.

KU812 CML ATCC 1,099 >10000

ML-2 AML DSMZ 687 136

MOLM13 A ML DSMZ 2647 >10000

MOLT-4 T-ALL ATCC 300 20

MV4: 11 AML ATCC 257 23

NOMO-1 AML DSMZ 62 5

RS4 ALL ATCC 205 16

THP-1 AMoL ATCC 1,599 >10000

U266 MM ATCC 1, 144 >10000

U-937 AML ATCC 679 62

Six of 16 cell lines, KG-1, NOMO-1, MV4: 11 AML, RS4 acute lymphocytic leukemia (ALL), MOLT-4 T-cell leukemia, and H929 multiple myeloma (MM) were highly sensitive to both Senexin B and Cortistatin A, whereas the other cell lines showed intermediate or low sensitivity. The concordance between the results obtained with Senexin B and Cortistatin A confirms that the sensitivity of leukemia cell lines was associated with CDK8/19 inhibition generally, and not the result of a particular CDK8/19 inhibitor. Figure IB shows the effects of Senexin B and Cortistatin A on the emergence of dead (Pi-positive) cells. Both CDK8/19 inhibitors were highly cytotoxic to 4 of the cell lines: H929, NOMO-1, MV4: 11 and RS4. Hence, CDK8/19 inhibition strongly inhibits cell growth and induces cell death in a subset of leukemias.

Example 2

Senexin B drastically increases the long-term efficacy of AraC in leukemia cells.

To determine if Senexin B and AraC have a synergistic effect in cells that are relatively insensitive to CDK8/19 inhibition, we treated the HL60 acute promyelocytic leukemia (APL) cell line with a series of concentrations of Senexin B and AraC alone and in combination, at a fixed molar ratio (1 AraC to 312.5 Senexin B). 7-day growth inhibitory effect was determined based on the number of Pi-negative cells as described in Example 1. The growth-inhibitory effects of the two drugs and their combination are shown in Figure 2. Compusyn

(www.combosyn.com) was used to compute the Combination Index (CI) of the drug

combination. The drugs are considered to be synergistic if the combination CI values are less than 1. The computed CI values for the AraC + Senexin B combination were 0.67 at ED50, 0.35 at ED75, 0.18 at ED90 and 0.12 at ED95. These results indicate that the combination is synergistic and that the synergy between the two drugs becomes especially pronounced at the highest drug combinations. The latter finding suggested that the potentiating effect of Senexin B on AraC could be due to preventing the emergence of resistance, which would have the greatest effect on cell growth and survival at the highest drug concentrations.

The appearance of resistant cells should have its principal effect on the cell growth upon long-term treatment, and therefore we determined the long-term effect of combining AraC and Senexin B. For this analysis, HL60 cells were plated in T-75 flasks, at 2 million cells in 20 ml of media (RPMI+10% FBS+Gln+Pen/Strep). The next day (day 1), cells were untreated or treated with 50 nM AraC, 2,500 nM Senexin B, or a combination of 50 nM AraC + 2,500 nM Senexin B. Drug treatment was conducted for 20 days (till day 21). Every 4 days cells were collected, counted using the high-throughput sampler in BD LSR II flow cytometer to determine the number of Pi-positive and Pi-negative cells and passaged at the same density (100,000 cells per ml) in fresh drug-containing media.

Figure 3A shows cell growth in this experiment presented as fold change in the calculated total number of live (Pi-negative) cells. After 20 days of treatment, AraC alone decreased the cell number by 2-3 orders of magnitude relative to the control, and Senexin B alone by 1-2 orders of magnitude. Strikingly, the combination of AraC and Senexin B decreased the cell number by 7 orders of magnitude. Notably, the number of live cells treated with the drug combination increased by day 5 but started decreasing on day 9 and the subsequent days. Figure 3B shows the same results presented as fraction of surviving drug-treated cells relative to the control. Figure 3C shows changes in the percentage of dead (Pi-positive cells) during the course of treatment. The dead cell fraction was uniformly low (4-5%) among Senexin B-treated cells. Among AraC -treated cells, the dead cell fraction increased from 14.6% on day 5 to 20-22% on days 9-13 but then started decreasing, down to 9.2% on day 21, indicating that selection of AraC-resistant cells was occurring. Strikingly, the dead cell fraction among cells treated with the AraC+Senexin B combination was 22.3% on day 5 but drastically increased to 76.2% on day 9 and stayed at a similar high level till day 21, indicating that a qualitative transition in the cellular effects of AraC + Senexin B combination occurred between 4 and 8 days of drug treatment, leading to virtual obliteration of leukemia cells.

Figure 4A shows the results of a similar experiment (conducted over 40 days of treatment), where AraC (50 nM) was combined with different concentrations of Senexin B or with 100 nM Cortistatin A. All the tested concentrations of Senexin B and Cortistatin A produced a drastic effect on HL60 cells when combined with AraC. Notably, cells treated with AraC alone developed resistance after approximately 12 days of treatment, but the development of resistance was delayed when AraC was combined with Senexin B or Cortistatin A, in a concentration-dependent manner, and the combination of AraC with the highest Senexin B concentration (2,000 nM) never developed the resistance in the course of the study.

Figure 4B compares the effects of AraC (50 nM) and Senexin B (tested at 2,000 nM) on the parental HL60 cells and HL60 cells selected (in the study shown in Fig. 4A) for resistance to 50 nM AraC. The AraC-selected cells show resistance to AraC alone but their response to Senexin B alone was even stronger than for the parental cells, and these cells retained a strong response to the combination of AraC and Senexin B. Hence, the combination of Senexin B and AraC should be beneficial for patients who have developed resistance following prior AraC therapy.

Figure 5 shows the results of a study similar to the one in Fig. 3, conducted with a different leukemia cell line, acute monocytic leukemia THP-1, over 60 days. THP-1 cells show only a weak response to either Senexin B (tested at 2,000 nM) or AraC (tested at 250 nM), but combining AraC and Senexin B strongly inhibited cell growth (Fig. 5A). In contrast to HL60, the effect of individual drugs and their combination was primarily cytostatic rather than cytotoxic (Fig. 5B), but it still produced a drastic decrease in the cell number.

Figure 6 shows the results of a study similar to the one in Fig. 3, conducted with still another AML cell line, U937, over 93 days. U937 cells are moderately sensitive to both Senexin B (tested at 1,000 nM) and AraC (tested at 25 nM). In the case of U937, no synergy between AraC and Senexin B was apparent until approximately 60 days of treatment, when cells treated with AraC alone developed resistance but cells treated with the combination of AraC and Senexin B continued to respond (Fig. 6A). While the individual drugs had a cytotoxic effect early in the experiment; the effect of the combination was primarily cytostatic (Fig. 6B).

We have also asked if combining AraC and Senexin B would have a beneficial effect on leukemia cells that are sensitive to CDK8/19 inhibition alone. In the study shown in Figure 7, MV4: 11 AML cells were treated for 60 days with 250 nM Senexin B or 50 nM AraC, individually or in combination. These cells showed almost no response to AraC but they were strongly inhibited by Senexin B until approximately 36 days of treatment when the cells developed resistance to this drug. However, the combination of Senexin B and AraC continued to be effective (Fig. 7A). The effect of the combination was associated with an increase in Senexin B-induced cell death in the presence of AraC (Fig. 7B). Hence, combining AraC with a CDK8 inhibitor is also beneficial for those leukemias that respond to the CDK8/19 inhibitor alone.

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