Modulators of HEC1 activity and methods therefor
Inventors
Huang, Jiann-Jyh • Chuang, Shih-Hsien • LEE, Ying-Shuan Eda • Huang, Yu-Ling • Lau, Johnson
Assignees
Development Center for Biotechnology • Taivex Therapeutics Corp
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Publication Number
US-11071736-B2
Publication Date
2021-07-27
Expiration Date
Abstract
Compounds, compositions, and methods for modulation of Hec1/Nek2 interaction are provided. Such compounds disrupt Nek2/Hec1 binding and may be useful as chemotherapeutic agents for neoplastic diseases.
Core Innovation
The invention relates to compounds having a structure according to Formula I, or pharmaceutically acceptable salts thereof. The Formula I structure is defined by substituent variables R1 through R5, with R1 as ORa or SRa, where Ra is a substituted or unsubstituted heteroaryl or a methoxyalkoxy substituted aryl. R2, R3, and R4 independently are hydrogen, C1-C6 alkyl or halogen, and R5 is heteroaryl, with each variable optionally substituted.
The disclosure further describes exemplified small-molecule structures and selected structural embodiments, including thiazolyl-isonicotinamide and related benzamide or carboxamide analogs. The examples vary substituents across the common scaffold, including hydroxy, methoxy, ethoxy, fluoro, cyano, dimethyl, and other substituted patterns, and include sulfoxide or sulfone analogs. The partial content also notes analytical characterization such as 1H NMR and ESI-MS data for multiple compounds and intermediates.
A related aspect covers a metabolite having a structure according to Formula I, with R1 defined as SRa, where SRa is a sulfone or a sulphoxide and Ra is a substituted or unsubstituted heteroaryl or a methoxyalkoxy substituted aryl. The claim set also includes pharmaceutical compositions comprising a carrier and a tosylate salt of the compound, and in one composition claim the compound is provided at an effective concentration to disrupt Hec1/Nek2 binding in a mammal upon administration.
Claims Coverage
The consolidated claim coverage includes four inventive features. The independent subject matters are a Formula I compound or pharmaceutically acceptable salt, a Formula I metabolite with R1 restricted to SRa as a sulfone or sulphoxide, a pharmaceutical composition comprising a carrier and a tosylate salt, and a pharmaceutical composition tied to disrupting Hec1/Nek2 binding in a mammal upon administration.
Formula I compound structure
A compound having a structure according to Formula I or a pharmaceutically acceptable salt thereof, wherein R1 is ORa or SRa; Ra is a substituted or unsubstituted heteroaryl or a methoxyalkoxy substituted aryl; R2, R3, and R4 independently are hydrogen, C1-C6 alkyl or halogen; R5 is heteroaryl; and each of R1, R2, R3, R4, and R5 is independently optionally substituted.
Formula I metabolite structure
A metabolite having a structure according to Formula I, wherein R1 is SRa, SRa is a sulfone or a sulphoxide, Ra is a substituted or unsubstituted heteroaryl or a methoxyalkoxy substituted aryl, R2, R3, and R4 are each independently hydrogen, C1-C6 alkyl, or halogen, R5 is heteroaryl, and each of R1, R2, R3, R4, and R5 is independently optionally substituted.
Pharmaceutical composition with tosylate salt
A pharmaceutical composition comprising a carrier and a tosylate salt of a compound having a structure selected from the group consisting of illustrated structures or selected compounds.
Pharmaceutical composition for disrupting Hec1/Nek2 binding
A pharmaceutical composition that includes a pharmaceutically acceptable carrier and the compound, optionally as a pharmaceutically acceptable salt, at an effective concentration to disrupt Hec1/Nek2 binding in a mammal upon administration.
Overall, the claims define a Formula I compound family by the permitted heteroaryl or methoxyalkoxy-substituted aryl choice for Ra, the ORa or SRa option at R1, and the allowed R2 to R4 and R5 substituent classes. The remaining independent claims define a corresponding metabolite and carrier-based pharmaceutical compositions, including a tosylate salt form and an administration-linked Hec1/Nek2 binding disruption objective.
Stated Advantages
Disrupting Hec1/Nek2 binding in a mammal upon administration.
Selective disruption of Hec1/Nek2 binding.
Inducing abnormal mitosis.
Causing apoptosis in cancer cells.
Producing downstream effects including caspase-3 and PARP cleavage.
Downregulating Mcl-1 and XIAP.
Altering cyclin B1 and cyclin D1.
Providing apoptosis-related readouts including sub-G1 apoptotic cells.
Antiproliferative activity is reported as IC50 on cancer cell lines, including sub-micromolar potency entries for some examples.
A pharmaceutical composition is provided that can disrupt Hec1/Nek2 binding in a mammal upon administration.
Documented Applications
A pharmaceutical composition effective to disrupt Hec1/Nek2 binding in a mammal upon administration.
Therapeutic use and combination use for neoplastic diseases.
Use in combination with a microtubule formation/degradation inhibitors drug class, including Taxol, vincristine, and vinblastine.
Assessment of antiproliferative activity against cancer cell lines, with IC50 values reported for HeLa, K562, MDA-MB-468, and MDA-MB-231.
Use of the claimed compound or pharmaceutical composition to disrupt Hec1/Nek2 binding in a mammal upon administration.
Antiproliferative activity evaluation of exemplary compounds on cancer cell lines including HeLa, K562, and MDA-MB-231, with results expressed as IC50 (μM).
Pharmaceutical composition for disrupting Hec1/Nek2 binding in a mammal upon administration.
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