The General Hospital Corporation

Dana-farber-cancer Institute Inc.

The Broad Institute, Inc.

Bristol-myers Squibb Compnay

Henry M Kronenberg

John T Potts, Jr

Thomas J Gardella

Harald T Juppner

David T Scadden

Laura Maria Calvi

Gregor Adams

Harald Jüppner

Gino V Segre

Abdul-Badi Abou-Samra

Ernestina Schipani

Naoto Shimizu

Nathanael Schiander Gray

Yanke Liang

Ramnik Xavier

Alykhan Shamji

Thomas Sundberg

Marc Wein

Hwan Geun Choi

Tomoko Doi

Harald J&uuml;ppner

Samuel R Nussbaum

John T Potts

The present disclosure provides methods of treating and/or preventing osteoporosis using salt-inducible kinase (SIK) inhibitors. Also provided are methods of using SIK inhibitors for increasing the function of osteocytes, increasing the number of osteoblasts, increasing the activity of osteoblasts, inhibiting the resorption of a bone, decreasing the number of osteoclasts, inhibiting the activity of osteoclasts, increasing the mass of a bone, down-regulating the expression of the gene SOST, and/or inhibiting the activity of sclerostin. The SIK inhibitors may be combined with Src inhibitors or CSF1R inhibitors. Exemplary SIK inhibitors include the compounds of the formula:

Uses of salt-inducible kinase (SIK) inhibitors for treating osteoporosis

The present disclosure provides methods of treating and/or preventing osteoporosis using salt-inducible kinase (SIK) inhibitors. Also provided are methods of using SIK inhibitors for increasing the function of osteocytes, increasing the number of osteoblasts, increasing the activity of osteoblasts, inhibiting the resorption of a bone, decreasing the number of osteoclasts, inhibiting the activity of osteoclasts, increasing the mass of a bone, down-regulating the expression of the gene SOST, and/or inhibiting the activity of sclerostin. The SIK inhibitors may be combined with Src inhibitors or CSF I R inhibitors. Exemplary SIK inhibitors include the compounds of the formula: (I), (II), (III), (IV), (V) or (VI). 

The invention relates to methods for manipulating hematopoietic stem or progenitor cells, mesenchymal stem cells, epithelial stem cells, neural stem cells and related products through activation of the PTH/PTHrP receptor in neighboring cells.

Parathyroid hormone receptor activation and stem and progenitor cell expansion

The present invention relates to conformationally constrained parathyroid hormone (PTH) analogs, and methods of preparing and using the PTH analogs. The invention provides novel PTH polypeptide derivatives containing amino acid substitutions at selected positions in the polypeptides. The invention provides derivatives of PTH(1-34), PTH(1-21), PTH(1-20), PTH(1-19), PTH(1-18), PTH(1-17), PTH(1-16), PTH(1-15), PTH(1-14), PTH(1-13), PTH(1-12), PTH(1-11), and PTH(1-10) polypeptides, wherein at least one residue in each polypeptide is a helix, preferably an &#x3b1;-helix, stabilizing residue. The invention also provides methods of making such peptides. Further, the invention encompasses compositions and methods for use in limiting undesired bone loss in a vertebrate at risk of such bone loss, in treating conditions that are characterized by undesired bone loss or by the need for bone growth, e.g., in treating fractures or cartilage disorders and for raising cAMP levels in cells where deemed necessary.

Conformationally constrained parathyroid hormone (PTH) analogs

Novel parathyroid hormone (PTH) polypeptide derivatives are disclosed, as are pharmaceutical compositions containing said polypeptides, and synthetic and recombinant methods for producing said polypeptides. Also disclosed are methods for treating mammalian conditions characterized by decreases in bone mass using therapeutically effective pharmaceutical compositions containing said polypeptides. Also disclosed are methods for screening candidate compounds of the invention for antagonistic or agonistic effects on parathyroid hormone receptor action. Also disclosed are diagnostic and therapeutic methods of said compounds.

Polypeptide derivatives of parathyroid hormone (PTH)

The present invention is related to novel parathyroid hormone polypeptide derivatives, and to pharmaceutical composition containing the polypeptides, as well as synthetic and recombinant methods for producing the polypeptides. Also disclosed are methods for treating mammalian conditions characterized by decreases in bone mass using therapeutically effective pharmaceutical compositions containing the polypeptides of the present invention. The present invention further provides diagnostic and therapeutic methods using the polypeptide derivatives.

Novel parathyroid hormone peptide (PTH) and parathyroid hormone related peptide (PTHrP) or derivatives thereof which are biologically active are disclosed, as are pharmaceutical compositions containing such peptides, and synthetic and recombinant methods for producing such peptides. Also disclosed are methods for treating mammalian conditions characterized by decreases in bone mass using therapeutically effective pharmaceutical compositions containing such peptides. Also disclosed are methods for screening candidate compounds of the invention for antagonistic or agonistic effects on parathyroid hormone receptor action. Also disclosed are diagnostic and therapeutic methods of such compounds.

Bioactive peptides and peptide derivatives of parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP)

The invention provides novel P1R polypeptide antagonists. These antagonists contain amino acid substitutions at selected positions in truncated PTH and PRHrP polypeptides and function by binding selectively to the juxtamembrane ('J') domain of the receptor. The J domain is the region of the receptor that spans the seven transmembrane domain and the extracellular loops.

Conformationally constrained parthyroid hormone (PTH) analogs

The present invention relates to conformationally constrained parathyroid hormone (PTH) analogs and derivatives of those analogs. The invention also provides methods of preparing and using the PTH analogs. Further, the invention encompasses compositions and methods for use in limiting undesired bone loss in a vertebrate at risk of such bone loss, in treating conditions that are characterized by undesired bone loss or by the need for bone growth, e.g. in treating fractures or cartilage disorders and for raising camp levels in cells where deemed necessary.

Conformationally constrained parathyroid hormones with alpha-helix stabilizers

The invention relates to methods for manipulating hematopoietic progenitor cells and related products. In one aspect the invention relates to the use of agents that activate a PTH/PTHrP receptor to enhance the growth and maintenance of hematopoietic progenitor cells in vivo and in vitro, to enhance mobilization of hematopoietic stem cells, to improve the efficiency of targeting cells to the bone marrow, and/or to modulate hematopoietic progenitor cell function.

Parathyroid hormone receptor activation and hematopoietic progenitor cell expansion

The present invention relates to methods of treatment of mammalian conditions characterized by decreases in bone mass with conformationally constrained parathyroid hormone (PTH) analogs and derivatives of those analogs containing PTH polypeptide derivatives containing at least one Glu or Lys substitution at position 6 and/or 10, some with installed lactam bridges between the side chains of Lys and Glu. The invention provides derivatives of PTH (1-34), PTH(1-33), PTH(1-32), PTH(1-31), PTH(1-30), PTH(1-29), PTH(1-28), PTH(1-27), PTH(1-26), PTH(1-25), PTH(1-24), PTH(1-23), PTH(1-22), PTH (1-21), PTH(1-20), PTH(1-19), PTH(1-18), PTH(1-17), PTH(1-16), PTH(1-15), PTH(1-14), PTH(1-13), PTH(1-12), PTH(1-11), PTH(1-10) and PTH(1-9) polypeptide. The invention also provides methods of preparing the PTH analogs. Further, the invention encompasses treating conditions that are characterized by undesired bone loss or by the need for bone growth, e.g. in treating fractures or cartilage disorders and for raising cAMP levels in cells where deemed necessary.

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Belmont, MA, United States of America

Henry M Kronenberg