Abstract: This invention relates to methods and compositions for treatment of inv (16) leukemia and particularly to treatment of acute myeloid leukemia. Disclosed is a method of treating inv (16) leukemia comprising the step of administering to a subject in in need thereof a therapeutically effective combination of a) a compound of the formula (1) (1) and b) a BRD4 inhibitor selected from the group consisting of JQ1, CeMMECZ, 1-BET 151 (or GSK1210151A), 1-BET 762 (or GSK525762), PFI-1, bromosporine, OTX-015 (or MK-8628), TEN-010, CPI-203, CPI-0610, RVX-208, BI2536, TG101348, LY294002, ABBV-075 (or mivebresib), FT-1101, ZEN003694, pharmaceutically acceptable salts and mixtures thereof. The therapeutically effective combination synergistically inhibits proliferation of inv (16) leukemia cells. This invention also relates to pharmaceutical compositions comprising a therapeutically effective combination of the compound of formula (1) and the BRD4 inhibitor and a pharmaceutically acceptable excipient.

Abstract: Provided are methods for treating a disease, disorder, or condition associated with an acid ceramidase (AC) biological activity. The methods include administering to a subject in need thereof a composition including an AC inhibitor and at least one additional active agent, such as a C6-ceramide nanoliposome (CNL); an inhibitor of a Bcl-2 family protein; a hypomethylating agent; an intensive chemotherapeutic agent such as cytarabine (AraC) and/or daunorubicin; a Hedgehog pathway inhibitor; a targeted agent, such as a FLT2 inhibitor or a EDH1/2 inhibitor; and/or an antibody drug conjugate that targets, for example, CD-33. The composition can include N-[(2S,3R)-1,3-dihydroxyoctadecan-2-yl]2-chloroacetamide (SACLAC) or a pharmaceutically acceptable salt thereof and at least one additional active agent. The disease, disorder, or condition associated with the AC biological activity can be a cancer, such as acute myeloid leukemia (AML).

Abstract: This invention relates to methods and compositions for treatment of inv(16) leukemia and particularly to treatment of acute myeloid leukemia. Disclosed is a method of treating inv(16) leukemia comprising the step of administering to a subject in need thereof a therapeutically effective combination of a) a compound of the formula (1) and b) a chemotherapeutic agent selected from the group consisting of pirarubicin, aclarubicin, mitoxantrone, doxorubicin, daunorubicin, idarubicin, epirubicin, cytarabine, pharmaceutically acceptable salts and mixtures thereof. The therapeutically effective combination synergistically inhibits proliferation of inv(16) leukemia cells. This invention also relates to pharmaceutical compositions comprising a therapeutically effective combination of the compound of formula (1) and the chemotherapeutic agent and a pharmaceutically acceptable excipient.

Abstract: This invention relates to methods and compositions for treatment of inv (16) leukemia and particularly to treatment of acute myeloid leukemia. Disclosed is a method of treating inv (16) leukemia comprising the step of administering to a subject in in need thereof a therapeutically effective combination of a) a compound of the formula (1) (1) and b) a BRD4 inhibitor selected from the group consisting of JQ1, CeMMECZ, 1-BET 151 (or GSK1210151A), 1-BET 762 (or GSK525762), PFI-1, bromosporine, OTX-015 (or MK-8628), TEN-010, CPI-203, CPI-0610, RVX-208, BI2536, TG101348, LY294002, ABBV-075 (or mivebresib), FT-1101, ZEN003694, pharmaceutically acceptable salts and mixtures thereof. The therapeutically effective combination synergistitally inhibits proliferation of inv (16) leukemia cells. This invention also relates to pharmaceutical compositions comprising a therapeutically effective combination of the compound of formula (1) and the BRD4 inhibitor and a pharmaceutically acceptable excipient.

Abstract: This invention relates to compounds that bind to wild-type CBF? and inhibit CBF? binding to RUNX proteins. The potent compounds of the invention inhibit this protein-protein interaction at low micromolar concentrations, using allosteric mechanism to achieve inhibition, displace wild-type CBF? from RUNX1 in cells, change occupancy of RUNX1 on target genes, and alter gene expression of RUNX1 target genes. These inhibitors show clear biological effects consistent with on-target RUNX protein activity. Pharmaceutical compositions containing a compound of the invention and a pharmaceutically acceptable carrier represent a separate embodiment of the invention. Another embodiment of the invention are methods of treating a RUNX-signaling-dependent cancer that expresses wild-type CBF? in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the invention.

Abstract: This invention relates to methods and compositions for treatment of inv(16) leukemia and particularly to treatment of acute myeloid leukemia. Disclosed is a method of treating inv(16) leukemia comprising the step of administering to a subject in need thereof a therapeutically effective combination of a) a compound of the formula (1) and b) a chemotherapeutic agent selected from the group consisting of pirarubicin, aclarubicin, mitoxantrone, doxorubicin, daunorubicin, idarubicin, epirubicin, cytarabine, pharmaceutically acceptable salts and mixtures thereof. The therapeutically effective combination synergistically inhibits proliferation of inv(16) leukemia cells. This invention also relates to pharmaceutical compositions comprising a therapeutically effective combination of the compound of formula (1) and the chemotherapeutic agent and a pharmaceutically acceptable excipient.

Abstract: This invention describes the development of targeted small molecule inhibitors of the inv(16) fusion, the causative agent in ˜12% of acute myeloid leukemia (AML). The inv(16) fusion results in expression of the CBF?-SMMHC fusion protein in the blood cells of afflicted patients. The present invention provides compounds which inhibit the function of both CBF? and the CBF?-SMMHC fusion. These compounds block the growth of an inv(16) leukemia cell line as well as increase its apoptosis, while showing minimal effects against non inv(16) cell lines. As a mechanism to develop inhibitors with selectivity for the CBF?-SMMHC fusion protein, the present invention further provides dimeric derivatives of these compounds which show both increased potency as well as selectivity for CBF?-SMMHC. These compounds show potent inhibition of an inv(16) leukemia cell line with minimal effects on non inv(16) cell lines.

Abstract: This invention relates to compounds that bind to wild-type CBF? and inhibit CBF? binding to RUNX proteins. The potent compounds of the invention inhibit this protein-protein interaction at low micromolar concentrations, using allosteric mechanism to achieve inhibition, displace wild-type CBF? from RUNX1 in cells, change occupancy of RUNX1 on target genes, and alter gene expression of RUNX1 target genes. These inhibitors show clear biological effects consistent with on-target RUNX protein activity. Pharmaceutical compositions containing a compound of the invention and a pharmaceutically acceptable carrier represent a separate embodiment of the invention. Another embodiment of the invention are methods of treating a RUNX-signaling-dependent cancer that expresses wild-type CBF? in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the invention.

Abstract: This invention describes the development of targeted small molecule inhibitors of the inv(16) fusion, the causative agent in ˜12% of acute myeloid leukemia (AML). The inv(16) fusion results in expression of the CBF?-SMMHC fusion protein in the blood cells of afflicted patients. The present invention provides compounds which inhibit the function of both CBF? and the CBF?-SMMHC fusion. These compounds block the growth of an inv(16) leukemia cell line as well as increase its apoptosis, while showing minimal effects against non inv(16) cell lines. As a mechanism to develop inhibitors with selectivity for the CBF?-SMMHC fusion protein, the present invention further provides dimeric derivatives of these compounds which show both increased potency as well as selectivity for CBF?-SMMHC. These compounds show potent inhibition of an inv(16) leukemia cell line with minimal effects on non inv(16) cell lines.

Abstract: This invention describes the development of targeted small molecule inhibitors of the inv(16) fusion, the causative agent in ˜12% of acute myeloid leukemia (AML). The inv(16) fusion results in expression of the CBF?-SMMHC fusion protein in the blood cells of afflicted patients. The present invention provides compounds which inhibit the function of both CBF? and the CBF?-SMMHC fusion. These compounds block the growth of an inv(16) leukemia cell line as well as increase its apoptosis, while showing minimal effects against non inv(16) cell lines. As a mechanism to develop inhibitors with selectivity for the CBF?-SMMHC fusion protein, the present invention further provides dimeric derivatives of these compounds which show both increased potency as well as selectivity for CBF?-SMMHC. These compounds show potent inhibition of an inv(16) leukemia cell line with minimal effects on non inv(16) cell lines.

Abstract: This invention describes the development of targeted small molecule inhibitors of the inv(16) fusion, the causative agent in ˜12% of acute myeloid leukemia (AML). The inv(16) fusion results in expression of the CBF?-SMMHC fusion protein in the blood cells of afflicted patients. The present invention provides compounds which inhibit the function of both CBF? and the CBF?-SMMHC fusion. These compounds block the growth of an inv(16) leukemia cell line as well as increase its apoptosis, while showing minimal effects against non inv(16) cell lines. As a mechanism to develop inhibitors with selectivity for the CBF?-SMMHC fusion protein, the present invention further provides dimeric derivatives of these compounds which show both increased potency as well as selectivity for CBF?-SMMHC. These compounds show potent inhibition of an inv(16) leukemia cell line with minimal effects on non inv(16) cell lines.

Abstract: This invention describes the development of targeted small molecule inhibitors of the inv(16) fusion, the causative agent in ˜12% of acute myeloid leukemia (AML). The inv(16) fusion results in expression of the CBF?-SMMHC fusion protein in the blood cells of afflicted patients. The present invention provides compounds which inhibit the function of both CBF? and the CBF?-SMMHC fusion. These compounds block the growth of an inv(16) leukemia cell line as well as increase its apoptosis, while showing minimal effects against non inv(16) cell lines. As a mechanism to develop inhibitors with selectivity for the CBF?-SMMHC fusion protein, the present invention further provides dimeric derivatives of these compounds which show both increased potency as well selectivity for CBF?-SMMHC. These compounds show potent inhibition of an inv(16) leukemia cell line with minimal effects on non inv(16) cell lines.

Abstract: This invention describes the development of targeted small molecule inhibitors of the inv(16) fusion, the causative agent in ˜12% of acute myeloid leukemia (AML). The inv(16) fusion results in expression of the CBF?-SMMHC fusion protein in the blood cells of afflicted patients. The present invention provides compounds which inhibit the function of both CBF? and the CBF?-SMMHC fusion. These compounds block the growth of an inv(16) leukemia cell line as well as increase its apoptosis, while showing minimal effects against non inv(16) cell lines. As a mechanism to develop inhibitors with selectivity for the CBF?-SMMHC fusion protein, the present invention further provides dimeric derivatives of these compounds which show both increased potency as well selectivity for CBF?-SMMHC. These compounds show potent inhibition of an inv(16) leukemia cell line with minimal effects on non inv(16) cell lines.