Activating mutations in fibroblast growth factor receptor 3 (FGFR3) and inactivating mutations in the natriuretic peptide receptor 2 (NPR2) guanylyl cyclase both result in decreased production of cyclic GMP (cGMP) and severe short stature, causing achondroplasia and acromesomelic dysplasia type Maroteaux, respectively. In attempt to find a new therapeutic approach for FGFR3-related skeletal disease, the inventors showed that a combination of a NPR2 agonist (e.g. BMN-111) and a phosphatase inhibitor (e.g. LB-100) significantly increases the length of the Fgfr3.sup.Y367C/+ femurs compared to Fgfr3.sup.+/+ femurs and improves the whole growth plate cartilage. The present invention thus relates to the use of a NPR2 agonist (e.g. BMN-111) and a phosphatase inhibitor (e.g. LB-100) for the treatment of FGFR3-related skeletal disease (e.g. achondroplasia).

Activating mutations in fibroblast growth factor receptor 3 (FGFR3) and inactivating mutations in the natriuretic peptide receptor 2 (NPR2) guanylyl cyclase both result in decreased production of cyclic GMP (cGMP) and severe short stature, causing achondroplasia and acromesomelic dysplasia type Maroteaux, respectively. In attempt to find a new therapeutic approach for FGFR3-related skeletal disease, the inventors showed that a combination of a NPR2 agonist (e.g. BMN-111) and a phosphatase inhibitor (e.g. LB-100) significantly increases the length of the Fgfr3.sup.Y367C/+ femurs compared to Fgfr3.sup.+/+ femurs and improves the whole growth plate cartilage. The present invention thus relates to the use of a NPR2 agonist (e.g. BMN-111) and a phosphatase inhibitor (e.g. LB-100) for the treatment of FGFR3-related skeletal disease (e.g. achondroplasia).

The present disclosure relates generally to modulators of Cot (cancer Osaka thyroid) and methods of use and manufacture thereof.

The present invention provides small-molecule inhibitors of BMP signaling and compositions and methods for inhibiting BMP signaling. These compounds and compositions may be used to modulate cell growth, differentiation, proliferation, and apoptosis, and thus may be useful for treating diseases or conditions associated with BMP signaling, including inflammation, cardiovascular disease, hematological disease, cancer, and bone disorders, as well as for modulating cellular differentiation and/or proliferation. These compounds and compositions may also be used to treat subjects with Sjögren's syndrome, or diffuse intrinsic pontine glioma (DIPG).

The present invention provides small-molecule inhibitors of BMP signaling and compositions and methods for inhibiting BMP signaling. These compounds and compositions may be used to modulate cell growth, differentiation, proliferation, and apoptosis, and thus may be useful for treating diseases or conditions associated with BMP signaling, including inflammation, cardiovascular disease, hematological disease, cancer, and bone disorders, as well as for modulating cellular differentiation and/or proliferation. These compounds and compositions may also be used to treat subjects with Sjögren's syndrome, or diffuse intrinsic pontine glioma (DIPG).

It is provided a cocrystal of a compound of formula (I) or of a compound formula (II) wherein X and Y are independently selected from —CH.sub.2— and —C(CH.sub.2)—, provided that al least one of X or Y is —CH.sub.2—; R.sup.1 is —CHCH.sub.3—Z.sub.m—W.sub.n—(CH.sub.2).sub.o-T.sub.p-S, wherein Z is O, and m is 0 or 1; W is R.sup.4CH CHR.sup.5, wherein either R.sup.4 and R.sup.5 are H and the dashed line indicates that there is a single bond, or R.sup.4 and R.sup.5 together are forming a bond and the dashed line indicates that there is a double bond, and n is 0 or 1; o is 0, 1 or 3; T is selected from the group consisting of —CHR.sup.6—, —C(O), wherein R.sup.6 is —OH or —CH.sub.3, and p is 0 or 1; S is selected from the group consisting of H, (C.sub.1-C.sub.3) alkyl optionally substituted by —OH, (C.sub.1-C.sub.3) haloalkyl optionally substituted by —OH, cyclopropyl, or; and R.sup.2 is —H or —OH; R.sup.3 is H or CH.sub.3; and the dashed line in formula (II) indicates a single or a double bond; and a hydrogen bond donor coformer which is a phenolic compound. It is also provided a composition comprising the cocrystal and a personal care product comprising the composition.

##STR00001##

A serum exosome with high osteogenesis and high angiogenesis, a preparation method and an application thereof are provided, which belongs to the field of bone defect repair technologies. The serum exosome is derived from a serum in a fracture recovery period, and the fracture recovery period is in a range of a second week to a fifth week after fracture. It has been found that the exosomes extracted from the serum after fracture have stronger osteogenic and angiogenic properties than exosomes extracted from normal serum, which is helpful to solve problems that large segmental bone defects, extensive traumas and other diseases are difficult to repair, and provide a new therapy for all diseases that need to be repaired and cured through osteogenic and/or angiogenic properties.

A serum exosome with high osteogenesis and high angiogenesis, a preparation method and an application thereof are provided, which belongs to the field of bone defect repair technologies. The serum exosome is derived from a serum in a fracture recovery period, and the fracture recovery period is in a range of a second week to a fifth week after fracture. It has been found that the exosomes extracted from the serum after fracture have stronger osteogenic and angiogenic properties than exosomes extracted from normal serum, which is helpful to solve problems that large segmental bone defects, extensive traumas and other diseases are difficult to repair, and provide a new therapy for all diseases that need to be repaired and cured through osteogenic and/or angiogenic properties.

The present invention provides a compound suitable for use as an acetyl CoA carboxylase (ACC) inhibitor, specifically, a thienopyridine derivative, and use of the compound in the preparation of drugs for treating metabolic disorders, cancers or other proliferative disorders, and nonalcoholic steatohepatitis (NASH).

Disclosed herein are adiponectin receptor agonists and methods of using the same for the treatment of inflammation or bone loss in a subject.