<PAGE>
                                                                   Exhibit 10.21

[*] CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY
    BRACKETS, HAS BEEN OMITTED AND FILED SEPARATELY WITH THE SECURITIES AND
    EXCHANGE COMMISSION PURSUANT TO RULE 406 OF THE SECURITIES EXCHANGE ACT OF
    1933, AS AMENDED.




                                           280 East Grand Avenue
                                           South San Francisco, CA 94080
[CYTOKINETICS LOGO]                        Tel (650) 624-3000 Fax (650) 624-3010




December 13, 2002



Glaxo Group Limited, doing business as GlaxoSmithKline
709 Swedeland Road
King of Prussia, Pennsylvania 19406
Attn:  Pradip K. Bhatnagar, Ph.D., Director, Genetic & Discovery Alliances


RE: DEFINITION OF TOOL COMPOUND AND USE THEREOF UNDER THAT CERTAIN
COLLABORATION AND LICENSE AGREEMENT BY AND BETWEEN GLAXO GROUP LIMITED, A
GLAXOSMITHKLINE COMPANY, ("GSK") AND CYTOKINETICS, INC. ("CK") OF EVEN DATE
JUNE 20, 2001 (THE "COLLABORATION AGREEMENT")

Dear Pradip:

Pursuant to this letter amendment to the Collaboration Agreement (the "Letter
Amendment"), GSK and CK desire to use certain tool compounds arising under the
Collaboration Agreement, all on the terms set forth herein.

Now therefore, GSK and CK agree, effective as of December 13, 2002 (the
"Letter Amendment Effective Date"), as follows:

     1.   All capitalized terms not defined herein shall have the meaning
          ascribed to them in the Collaboration Agreement.

     2.   A "Tool Compound" shall mean any Compound, including but not limited
          to [*] and [*], not designated nor intended to be designated as a
          Development Compound, and that the JRC has approved for distribution
          to Third Parties for the conduct of studies that may result in the
          subsequent publication of the results of such studies; provided that,
          such results are not to be reportable to the FDA. At the time of such
          approval by the JRC, the composition of matter and method of use of
          such Tool Compound shall be covered by a Patent within the Licensed
          Technology.

     3.   The JRC may amend the definition of Tool Compound at any time, such
          amendments to be reflected in agreed and approved minutes of JRC
          meetings; provided, once a Compound has met the definition of Tool
          Compound it shall remain a Tool Compound, unless and until otherwise
          mutually agreed in writing by the Parties.


* Certain information on this page has been omitted and filed separately with
  the Commission. Confidential treatment has been requested with respect to the
  omitted portions.
<PAGE>
Pradip K. Bhatnagar, Ph.D.
December 13, 2002
Page Two

      4.    Notwithstanding Sections 1.13, 1.53 and 5.7, and the restrictions
            on use and disclosure set forth in Sections 4.1 and 9.5, of the
            Collaboration Agreement, each Party shall have the right to use
            Tool Compounds, and information relating thereto, outside the
            Research Program for the sole purpose of generating negative control
            information in studies directed to the research, discovery and
            development of compounds based on their activity in directly
            modulating a target other than a Mitotic Kinesin Target, and
            Collaboration Technology and/or Post-Collaboration Technology shall
            not include any inventions and/or results that arise from such use.

      5.   Except as specifically modified or amended hereby, the Collaboration
           Agreement shall remain, in full force and effect and, as modified or
           amended, is hereby ratified, confirmed and approved. No provision of
           this Letter Amendment may be modified or amended except expressly in
           a writing signed by both Parties nor shall any terms be waived except
           expressly in a writing signed by the Party charged therewith. This
           Letter Amendment shall be governed in accordance with the laws of the
           [*], without regard to principles of conflicts of laws.

Please sign and return two copies of this letter if you agree to the foregoing
terms.

Sincerely,

/s/ Robert I. Blum

Robert I. Blum
Senior Vice President, Finance and Corporate Development
Chief Financial Officer
Cytokinetics, Inc.

Agreed and accepted:

GLAXO GROUP LIMITED

/s/ Pradip Bhatnagar

Name: Pradip Bhatnagar, Ph.D.

Title: Alliance Management, Director

cc: Vice President, Business Development, Glaxo Group Limited, doing business
    as GlaxoSmithKline
    Senior Vice President and Assistant General Counsel-R&D Legal Operations,
    GlaxoSmithKline Corporate Legal Department
    Kenneth A. Clark, Esq., Wilson Sonsini Goodrich & Rosati Professional
    Corporation

* Certain information on this page has been omitted and filed separately with
  the Commission. Confidential treatment has been requested with respect to the
  omitted portions.