Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-12-31
2004-08-03
Russel, Jeffrey Edwin (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C514S013800, C514S014800, C514S016700, C514S017400, C530S327000
Reexamination Certificate
active
06770626
ABSTRACT:
FIELD OF THE INVENTION
The present invention concerns methods and compounds for changing (modulating) tissue-remodeling processes.
BACKGROUND OF THE INVENTION
The eukaryotic protein kinase superfamily is composed of enzymes which specifically phosphorylate serine, threonine or tyrosine residues of intracellular proteins. These enzymes are important in mediating signal transduction in multicellular organisms and are involved in a wide variety of cellular events. A few examples include: cellular proliferation, cellular differentiation, oncogenesis, immune responses, and inflammatory responses.
Enhanced protein kinase activity can lead to persistent stimulation by secreted growth factors and other growth inducing factors which, in turn, can lead to proliferative diseases such as cancer, to nonmalignant proliferative diseases such as arteriosclerosis, psoriasis and to inflammatory responses such as septic shock. Decreased function can also lead to disease. For example, a decrease in the activity of insulin receptor kinase is a cause of various types of diabetes.
Thus, agents which can modulate (increase or decrease) the activity of protein kinases have great potential for the treatment of a wide variety of diseases and conditions such as cancer, autoimmune disorders, and inflammation.
PKs are known to have homologous “catalytic domains” which are responsible to the phosphorylation activity. Based on a comparison of a large number of protein kinases, it is now known that the kinase domain of protein kinases can be divided into twelve subdomains. These are regions that are generally uninterrupted by large amino acid insertions and contain characteristic patterns of conserved residues (Hanks and Hunter, “The Eukaryotic Protein Kinase Superfamily”, in Hardie and Hanks ed., The Protein Kinase Facts Book, Volume I, Academic Press, Chapter 2, 1995). These subdomains are referred to as Subdomain I through Subdomain XII.
Due to the high degree of homology found in the subdomains of different protein kinases, the amino acid sequences of the domains of different PKs can be aligned. Frequently, the alignment is carried out with reference to the prototypical protein kinase PKA-C&agr;, as known in the art. Currently, the catalytic domains of a large number of protein kinases have been aligned and tables showing these alignments are available from various published sources, such as, for example, in the article by Hanks and Quinn in Methods of
Enzymology
200: 38-62 (1991) or in the PKR Web Site: www.sdsc.edu/kinases.
U.S. Pat. No. 6,174,993, International Application WO 98/53051 (corresponding to pending U.S. Application 08/861,153), International Application WO 00/118895 (corresponding to U.S. Ser. No. 09/161,094, now abandoned), U.S. applications Ser. No. 09/458,491, now abandoned (corresponding to WO 01/42280), and U.S. Ser. No. 09/734,520, now abandoned (corresponding to WO 02/48336) (all incorporated herein by reference) concern small, previously undisclosed, regions of various protein kinases with high substrate specificity. Short peptides derived from these regions were found to modulate kinase activities, as determined by the modulation of cellular activity in various in vivo and in vitro models. Without wishing to be bound by theory it is assumed that the short peptides disclosed in these applications, mimic some region of the catalytic domain of the kinase, bind to other cellular components with which the kinase interacts (such as the substrates of the kinase, other kinases, other phosphatases) and thus modulate kinase activity either by mimicking the kinase activity, or alternatively by inhibiting the interaction of the kinase and the cellular components thus inhibiting kinase-mediated signaling.
U.S. Pat. No. 6,174,993 and WO 98/53051 disclose a domain termed the HJ-loop. The “HJ-loop” referred to therein is found within the kinase domain of protein kinases between the middle of Subdomain IX and the middle of Subdomain X. Because of the high degree of homology found in the subdomains of different protein kinases, the amino acid sequences of the domains of different ser/thr protein kinases can be aligned. Thus, the HJ-loop of protein kinases can be defined by reference to the amino acid sequence of a prototypical protein kinase, for example PKA-C&agr;, and can be said to correspond to a contiguous sequence of about twenty amino acid residues found between about amino acid 229 and 248 of PKA-C&agr;.
A second definition of the HJ loop of protein kinases, which is complementary to the definition provided in the proceeding paragraph, can be made by reference to the secondary structure of the kinase domain of protein kinases. The kinase domain of protein kinases has been found to contain at least nine alpha helices, referred to as helix A through helix I, nine beta sheets, referred to as b1 through b9 (Tabor et al.,
Phil. Trans. R. Soc. Lond
. B340: 315 (1993), Mohammadi et al.,
Cell
86:577 (1996) and Hubbard et al.,
Nature
372:746 (1994)). The HJ loop is a contiguous sequence of about twenty amino acids beginning within the F helix about five amino acids residues from the N-terminus of the F helix and extending about five amino acid residues into the G helix. It is noteworthy that the HJ-loop of the TGF-&bgr;/ILK family of protein kinases contains an insertion of about 12 to 15 extra amino acids as compared to other ser/thr or tyrosine (tyr) protein kinases.
WO 02/48336 discloses a region termed the “A-region”. The “A-region” referred to herein is found within the kinase domain of PKs in Subdomain III and Subdomain IV. With respect to the amino acid sequence of the prototypical protein kinase PKA-C&agr; the A region can be said to correspond to a contiguous sequence of about eighteen amino acid residues found between about amino acids 92 and 109 of PKA-C&agr;. In some PKs, extra amino acids can be present in this region and the size of the A-region can, therefore, include more than 18 amino acids in length.
With respect to the secondary structure of protein kinases, the A region is a contiguous sequence of about five to twenty amino acids beginning at the middle of the &agr;C helix (hereby &agr;C) and ending at the beginning of the b4 beta sheet.
WO 01/42280 discloses a region termed B4-B5 region. The “B4-5 region” referred to herein is found within the kinase domain of PKs in Subdomain IV and the beginning of Subdomain V. With respect to the amino acid sequence of the prototypical protein kinase PKA-C&agr;, the B4-5 region can be said to correspond to a contiguous sequence representing the amino acid residues found between about amino acids 106 and 114 of PKA-C&agr;.
In some PKs, extra amino acids might be inserted in this region and the size of the B4-5 region can, therefore, include more than 9 amino acids in length.
A second definition of the B4-5 region of a PK, which is complementary to the definition provided in the preceding paragraph, can be made by reference to the three dimensional structure of the kinase domain of PKs. The kinase domain of PKs has been found to contain at least nine alpha helices, referred to as helix A through helix I and nine beta sheets, referred to as b1 through b9 (Tabor et al.,
Phil. Trans. R. Soc. Lond
., B340: 315 (1993), Mohammadi et al., Cell, 86:577 (1996) and Hubbard et al., Nature 372:746 (1994). The B4-5 region is a contiguous sequence of about five to twenty five amino acids beginning at the end of the b4 beta sheet and into the b5 beta sheet.
WO 00/18895 discloses a region termed the “&agr;D region”. The “&agr;D region” referred to herein is found within the kinase domain of PKs in Subdomain V and the beginning of Subdomain VI. The “&agr;D region” of a PK can be defined by reference to the amino acid sequence of a prototypical protein kinase, for example PKA-C&agr; and can be said to correspond to a contiguous sequence of about twenty amino acid residues found between about amino acid 120 and 139 of PKA-C&agr;.
In relation to the secondary structure of the kinase domain of PKs, the &agr;D region is a contiguous sequence of about fifteen
Browdy and Neimark , P.L.L.C.
Children's Medical Center Corporation
Russel Jeffrey Edwin
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